Interferon and lamivudine combination therapy versus lamivudine monotherapy for hepatitis B e antigen-negative hepatitis B treatment:a meta-analysis of randomized controlled trials

BACKGROUND: It has been demonstrated that only a minority of patients with hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) obtain a sustained response after either interferon (IFN) or nucleos (t)ide analogue monotherapy. Therefore, combination therapy of drugs with synergistic antiviral effects was proposed to have a sustained response in these patients. We compared the effect and safety of lamivudine monotherapy and its combination with IFN including conventional interferon (CON-IFN) and pegylated interferon (PEG-IFN) for HBeAg-negative CHB patients. DATA SOURCES: A group of three independent reviewers identified 9 eligible randomized controlled trials through electronic searches (MEDLINE, OVID, EMBASE, the Cochrane Library Clinical Trials Registry, and the Chinese Medical Database), manual searches, and contact with experts. Sustained virological and biochemical responses were defined as primary efficacy measures. We performed quantitative meta-analyses to assess differences between CON-IFN plus lamivudine combination and lamivudine monotherapy groups. RESULTS: No greater sustained virological and biochemical rates were found in patients receiving CON-IFN/lamivudine combination therapy [29.1% vs. 26.7%, odds ratio (OR)=0.98, 95% confidence interval (CI) 0.65-1.50, P=0.94, and 41.8% vs. 40.3%, OR=1.13, 95% CI 0.78-1.65, P=0.51, respectively],though a reduced YMDD mutation rate was achieved in the combination group [8.39% vs. 30.0%, OR=0.16, 95% CI 0.076-0.33, P<0.001]. However, data from one PEG-IFN trial showed greater sustained virological and biochemical rates in patients receiving combination therapy [response rate 19.5% vs. 6.6%, OR=3.42, 95% CI 1.71-6.84, P<0.001 and 60.0% vs. 44.2%, OR=1.88, 95% CI 1.23-2.85, P=0.003, respectively]. CONCLUSIONS: Addition of CON-IFN to lamivudine did not improve treatment efficacy but suppressed YMDD mutation by lamivudine. Combination of PEG-IFN and lamivudine might increase the sustained response, and further clinical trials are needed for confirmation.

Interferon-伪 plus lamivudine vslamivudine reduces breakthroughs, but does not affect sustained response in HBeAg negative chronic hepatitis B

AIM： To investigate the efficacy of combination treatment of IFN-α and lamivudine compared to lamivudine monotherapy, after 24 mo of administration in HBeAgnegative hepatitis B patients. METHODS： Fifty consecutive patients were randomly assigned to receive IFN-α-2b （5 MU thrice per week, n = 24） plus lamivudine （100 mg daily） or lamivudine only （n = 26） for 24 mo. Patients were followed up for further 6 mo. The primary outcome was the proportion with sustained virological response （undetectable serum HBV DNA concentrations） and or sustained biochemical response （transaminase levels within normal range） at 30 mo （6 mo after the end of therapy）. Secondary end-points were timed from initial virological （biochemical） response to VBR （BBR, respectively） and the emergence of YMDD mutants across the two arms. RESULTS： Five of twenty-four （21%） patients in the combination arm vs 3/26 （12%） in the lamivudine arm had sustained response （i.e., normal serum transaminase levels and undetectable HBV DNA by PCR assay） 6 mo after treatment discontinuation. A reduction in the emergence of YMDD mutants and in the development of virological breakthroughs was observed in patients receMng combination treatment （10% vs46% , P= 0.01 and 14% vs46% , P= 0.03, respectively）. Time from initial virologic response to virologic breakthrough （VBR） was greater among initial responders receiving combination treatment compared to those receiving lamivudine （22.9 mo vs 15.9 mo, respectively; P = 0.005）.CONCLUSION： Our results demonstrate that IFN-α plus lamivudine combination therapy does not increase the sustained response, compared to lamivudine. However, combination therapy reduces the likelihood of VBR due to YMDD mutants and prolongs the time period until the breakthrough development.

Relationship between serum b2-microglobulin levels and virological breakthrough in HBeAg-negative chronic hepatitis B patients,under long-term treatment schedules including lamivudine

AIM: Predictive value of serum b2-microglobulin (b2m)levels for virological breakthrough (VB) in HBeAg-negative chronic hepatitis B (CHB) patients under long-term treatment schedules including lamivudine (LAM).METHODS: Serum b2m levels were calculated during treatment in 25 CHB patients under long-term LAM monotherapy (group A) and 12 patients under initial interferon plus LAM treatment followed by LAM monotherapy (group B), using the MEIA technology. We used Cox proportional hazard models in order to investigate the association between serum b2m levels and VB.RESULTS: Seven of 25 patients (28%), 9/25 (36%) and 14/25 (56%) from group A and 0/12, 2/12 (16.6%) and 3/12 (25%) from group B exhibited VB at months 12, 24 and 36 of treatment, respectively. All patients, from both groups, who did not show VB exhibited b2m elevation in mo 3. The duration of b2m elevation was significantly longer in the virological responder's subgroup from group A than the non-responder's one (7.3±2.6 vs 3.8±3.4 mo,P = 0.02). In comparison to group A patients whose b2m levels were increased at 3 mo, patients whose b2m levels were decreased had 4.6 times higher risk of experiencing VB (RR = 4.6, P = 0.024). When baseline variables were simultaneously included in the same Cox model, decreased b2m status was still associated with increased risk of VB (RR = 12.2, P = 0.03).CONCLUSION: In HBeAg-negative CHB patients under either long-term LAM monotherapy or initial combination treatment, serum b2m levels at 3 mo of treatment,compared to baseline ones, might be a predictor of risk for VB.

Combination Therapy with Pegylated Interferon alpha-2b and Adefovir Dipivoxil in HBeAg-positive Chronic Hepatitis B versus Interferon Alone: A Prospective, Randomized Study

Currently available monotherapies of oral nucleoside/nucleotide analogs or interferon are unable to achieve a sustained and effective response in most of patients with chronic hepatitis B（CHB）. The objective of the present study was to compare the efficacy and safety of pegylated interferon（Peg-IFN） alpha-2b plus adefovir dipivoxil combination therapy versus Peg-IFN alpha-2b alone. Sixty-one HBeAg-positive chronic hepatitis B patients were randomized to receive Peg-IFN alpha-2b alone（1.5 μg/kg once weekly） or Peg-IFN alpha-2b plus adefovir（10 mg daily） for up to 52 weeks. Efficacy and safety analyses were performed on all participants who received at least one dose of study medication. The rate of HBeAg seroconversion and undetectable HBV-DNA were evaluated after 52 weeks of therapy. At the end of treatment, 11 of 30（36.7%） patients receiving combination therapy achieved HBeAg seroconversion versus 8 of 31（25.8%） in the monotherapy group（P=0.36）. In contrast, the percentage of patients with undetectable serum HBV DNA was significantly higher in the combination group than in the monotherapy group（76.7% vs. 29.0%, P〈0.001）. Thyroid dysfunction was more frequent in the combination group than in the monotherapy group（P〈0.05）. In HBeAg-positive CHB, combination of Peg-IFN alpha-2b and adefovir for 52 weeks resulted, at the end of treatment, in a higher virological response but without significant impact on the rate of HBeAg seroconversion and possibly an adverse effect on thyroid function.

Pegylated interferon α-2b up-regulates specific CD8+ T cells in patients with chronic hepatitis B

AIM:To investigate the effect of pegylated interferon (IFN) α-2b on specific CD8+ T lymphocytes in patients with chronic hepatitis B (CHB). METHODS:Twenty-one patients with CHB were treated with pegylated IFN α-2b. Periphery blood mononuclear cells were isolated from fresh heparinized blood by Ficoll-Hypaque density gradient centrifugation (density:1.077 g/L,Pharmingen) at weeks 0,4,8,12,and 24,respectively. Frequency of circulating hepatitis B virus (HBV) epitope-specific CD8 T cells was detected by flow cytometry. Cytokines were detected by cytometric bead assay. RESULTS:The frequency of circulating HBV core or env-specific CD8 T cells was higher (P < 0.05),the number of HBV core specific CD8 T cells was greater at week 24 (P < 0.05),the level of Th1-type cytokines [interleukin (IL)-12,tumor necrosis factor-α,and IFN-γ] was higher,while that of Th2-type cytokines (IL-4,IL-6,and IL-10) was lower in responders than in nonresponders (P < 0.05) after pegylated IFN α-2b treatment. The IL-6 level was correlated with HBV DNA (r = 0.597,P = 0.04),while the inducible protein-10 (IP-10) level was correlated with serum alanine aminotransferase (ALT) (r = 0.545,P = 0.005). The IP-10 level at week 8 after pegylated IFN α-2b treatment could predict the normalization of ALT in CHB patients (positive predict value = 56%,negative predict value = 92%). CONCLUSION:Pegylated IFN α-2b can enhance the immune response of CHB patients by increasing the frequency of HBV specific CD8+ T cells and regulating the Th1/Th2 cytokines.

Add-on pegylated interferon augments hepatitis B surface antigen clearance vs continuous nucleos(t)ide analog monotherapy in Chinese patients with chronic hepatitis B and hepatitis B surface antigen≤1500 IU/mL:An observational study

BACKGROUND Nucleos(t)ide analog(NA)has shown limited effectiveness against hepatitis B surface antigen(HBsAg)clearance in chronic hepatitis B(CHB)patients.AIM To evaluate the efficacy and safety of add-on peginterferonα-2a(peg-IFNα-2a)to an ongoing NA regimen in CHB patients.METHODS In this observational study,195 CHB patients with HBsAg≤1500 IU/m L,hepatitis B e antigen(HBeAg)-negative(including HBeAg-negative patients or HBeAg-positive patients who achieved HBeAg-negative after antiviral treatment with NA)and hepatitis B virus-deoxyribonucleic acid<1.0×10^2 IU/mL after over 1 year of NA therapy were enrolled between November 2015 and December2018 at the Second Affiliated Hospital of Xi'an Jiaotong University,China.Patients were given the choice between receiving either peg-IFNα-2a add-on therapy to an ongoing NA regimen(add-on group,n=91)or continuous NA monotherapy(monotherapy group,n=104)after being informed of the benefits and risks of the peg-IFNα-2a therapy.Total therapy duration of peg-IFNα-2a was 48 wk.All patients were followed-up to week 72(24 wk after discontinuation of peg-IFNα-2a).The primary endpoint was the proportion of patients with HBsAg clearance at week 72.RESULTS Demographic and baseline characteristics were comparable between the two groups.Intention-to-treatment analysis showed that the HBsAg clearance rate in the add-on group and monotherapy group was 37.4%(34/91)and 1.9%(2/104)at week 72,respectively.The HBsAg seroconversion rate in the add-on group was 29.7%(27/91)at week 72,and no patient in the monotherapy group achieved HBsAg seroconversion at week 72.The HBsAg clearance and seroconversion rates in the add-on group were significantly higher than in the monotherapy group at week 72(P<0.001).Younger patients,lower baseline HBsAg concentration,lower HBsAg concentrations at weeks 12 and 24,greater HBsAg decline from baseline to weeks 12 and 24 and the alanine aminotransferase≥2×upper limit of normal during the first 12 wk of therapy were strong predictors of HBsAg clearance in patients with peg-IFNα-2a add-on treatment.Regarding the safety of the treatment,4.4%(4/91)of patients in the add-on group discontinued peg-IFNα-2a due to adverse events.No severe adverse events were noted.CONCLUSION Peg-IFNα-2a as an add-on therapy augments HBsAg clearance in HBeAg-negative CHB patients with HBsAg≤1500 IU/m L after over 1 year of NA therapy.

Effect of switching from treatment with nucleos(t)ide analogs to pegylated interferon α-2a on virological and serological responses in chronic hepatitis B patients

AIM To investigate the efficacy of switching to pegylated interferon-α-2a(Peg IFNα-2a) treatment in nucleos(t)ide analog(NA)-treated chronic hepatitis B(CHB) responder patients. METHODS A 48-wk prospective and retrospective treatment trial of NA-treated CHB patients who had received entecavir(ETV) for at least 48 wk and had serum hepatitis B virus(HBV)-DNA < 500 IU/m L, serum hepatitis B envelope antigen(HBe Ag) < 100 S/CO, serum alanine aminotransferase, and aspartate aminotransferase levels < 2 × the upper limit of normal of 40 IU/L was performed. The effects on virological and serological responses and adverse reactions to 0.5 mg daily ETV for 48 wk vs switching to Peg IFNα-2a were compared. Forty-four patients were randomized to be switched from NA treatment to the Peg IFNα-2a group, and 44 patients were simultaneously randomized to the ETV group. RESULTS After 48 wk of therapy, the decrease in hepatitis B surface antigen(HBs Ag) levels was greater in the Peg IFNα-2a group than in the ETV group(3.1340 log10 IU/m L vs 3.6950 log10 IU/m L, P = 0.00). Seven patients who were anti-HBs-positive at baseline achieved HBs Ag loss when switched to Peg IFNα-2a(15.91% vs 0%,P = 0.018). The HBe Ag serological conversion rate was higher in the Peg IFNα-2a group than in the ETV group; however, the difference was not significant because of the small sample sizes(34.38% vs 21.88%, P = 0.232). In the Peg IFNα-2a group, patients with HBs Ag levels < 1500 IU/m L at baseline had higher HBe Ag seroconversion and HBs Ag loss rates at week 48 than those with HBs Ag levels ≥ 1500 IU/m L(HBe Ag seroconversion: 17.86% vs 62.5%, P = 0.007; HBs Ag loss: 41.67% vs 6.25%, P = 0.016). Moreover, patients with HBs Ag levels < 1500 IU/m L at week 24 had higher HBs Ag loss rates after therapy than those with HBs Ag levels ≥ 1500 IU/m L(36.84% vs 0%, P = 0.004). However, there were no statistically significant differences in HBe Ag seroconversion rates(47.06% vs 25.93%, P = 0.266). CONCLUSION NA-treated CHB patients switched to sequential Peg IFNα-2a achieved highly potent treatment termination safely.

Effects of interferon α-2b on liver function, complement level and oxidative stress in patients with hepatitis B

Objective:To observe the effect of interferonα-2b treatment on liver function,liver fibrosis,complement protein and oxidative stress in patients with hepatitis B.Methods:A total of 100 patients with hepatitis B in our hospital were randomly divided into the control group and the observation group,with 50 cases in each group.After admission,patients in the control group were treated with entecavir,while patients in the observation group were treated with interferonα-2b combined with entecavir.The levels of serum total bilirubin(TBil),aspartate aminotransferase(AST),alanine aminotransferase(ALT),type III procollagen(PCIII),type IV collagen(CIV),complement C3 protein(C3),complement C4 protein(C4),malondialdehyde(MDA),superoxide dismutase(SOD)and nitric oxide(NO)were compared between the two groups before and after treatment.Results:After treatment,the levels of TBil,AST,ALT,PCIII,CIV,MDA and NO in serum of patients with hepatitis B in both groups were significantly lower than those before treatment,and the levels of C3,C4 and SOD were significantly higher than those before treatment(P<0.05).After treatment,the levels of TBil,AST,ALT,PC III,C IV,MDA and NO in serum of patients in the observation group were significantly lower than those in the control group,while the levels of C3,C4 and SOD in serum of patients in the observation group were significantly higher than those in the control group(P<0.05).Conclusions:The combination of interferonα-2b and entecavir has a good curative effect on hepatitis B.It can significantly improve the liver function and immune function of patients,delay the process of liver fibrosis and reduce oxidative stress injury.It is worthy of clinical promotion.

干扰素α-2b联合拉米夫定对乙肝患者细胞免疫、肝功能及乙型肝炎病毒含量变化的影响

目的探究干扰素α-2b联合拉米夫定对乙肝患者细胞免疫、肝功能及乙型肝炎病毒含量变化的影响。方法以乙肝患者100例作为研究对象,随机分为两组,每组各50例。对照组给予拉米夫定,观察组在对照组的基础上给予干扰素α-2b治疗。治疗前及治疗1年后抽晨起静脉血检测细胞免疫、肝功能及HBV-DNA含量水平的变化。应用SPSS 18.0软件,所获数据采用方差分析和t检验。结果对照组治疗前、后CD_3^+指标变化比较,P>0.05;对照组治疗前后CD_4^+、CD_8^+指标变化比较,P<0.0005。观察组治疗前后CD_3^+指标变化比较,P<0.0005;观察组治疗前后CD_8^+指标变化比较,P<0.05;观察组治疗前后CD_4^+指标变化比较,P>0.05。两组治疗后CD_3^+指标变化比较,P<0.0005;两组治疗后CD_4^+指标变化比较,P<0.005;两组治疗后CD_8^+指标变化比较,P<0.001。对照组治疗前后ALT、AST、HbeAg、HBV-DNA水平变化比较,P均<0.0005。观察组治疗前后ALT、AST、HbeAg、HBV-DNA水平变化比较,P均<0.0005。两组治疗后ALT、AST水平变化比较,P均<0.05;两组治疗后HbeAg、HBV-DNA水平变化比较,P均<0.0005。结论干扰素α-2b联合拉米夫定治疗乙肝有助于改善T淋巴细胞免疫力,改善肝功能及降低HBV-DNA含量。

干扰素α2b联合拉米夫定治疗慢性乙型肝炎患者血清HBeAg阴转和肝功能的变化

目的分析抗病毒治疗对慢性乙型肝炎患者HBe Ag阴转及肝功能的影响。方法选择2013年2月至2013年11月在本院进行治疗的慢性乙型肝炎患者130例,随机分为观察组和对照组各65例。给予对照组患者干扰素α2b治疗,观察组在此基础上联合拉米夫定治疗。采用ELISA法检测血清乙型肝炎病毒标记物;采用实时荧光定量PCR法检测HBV DNA,分别在治疗6个月和12个月观察患者肝功能、HBV DNA阴转率和HBe Ag转阴率的变化。结果在治疗6个月时,观察组谷丙转氨酶和谷草转氨酶水平分别为(45.7±23.8)U/L和(62.3±23.7)U/L,显著低于对照组的[(55.8±25.3)U/L和(73.2±25.3)U/L,P<0.05];在治疗12个月时,观察组谷丙转氨酶和谷草转氨酶水平分别为(32.7±19.4)U/L和(46.4±6.3)U/L,显著低于对照组的[(44.6±17.3)U/L和(52.8±5.2)U/L,P<0.05];两组患者血清HBV DNA阴转率和HBe Ag阴转率的差异无统计学差异(P>0.05)。结论抗病毒治疗能够有效地改善慢性乙型肝炎患者肝功能,促进HBe Ag阴转,使用干扰素α2b联合拉米夫定治疗的效果更为显著,且安全性较高。

干扰素α-1b和拉米夫定序贯治疗慢性乙型肝炎的高水平HBV清除动力学观察

目的观察干扰素α-1b(IFNα-1b)和拉米夫定序贯治疗对慢性乙型肝炎的高水平复制HBV清除动力学的影响。方法76例HBeAg阳性且HBV DNA>1×107copies/ml慢性乙型肝炎患者随机分为治疗组和对照组。治疗组40例,先用拉米夫定治疗4周,再加用IFNα-1b治疗8周,然后单用IFNα-1b治疗16周,对照组36例单用IFNα-1b治疗24周。分别于治疗前后定期检测肝功能、血常规、乙肝标志物及HBV DNA。结果治疗结束时,治疗组的ALT复常率、HBV DNA阴转率、HBeAg阴转率及抗-HBe阳转率均明显高于对照组(P<0.05,P<0.01),治疗组有效率(72.5%)明显高于对照组(50.0%)(P<0.05)。治疗期间两组的副反应无明显的差异(P>0.05)。随访6个月治疗组的上述指标仍高于对照组(P<0.05),仅两组间的抗-HBe阳转率差异无显著性(P>0.05)。结论IFNα-1b和拉米夫定序贯治疗对HBV高水平复制的慢性乙型肝炎有较好的效果,优于单用IFNα-1b治疗。

拉米夫定在IFN-α经治HBeAg阳性慢性乙肝患者中的疗效观察

目的:探讨拉米夫定(LMV)治疗干扰素(IFN-α)经治HBeAg阳性慢性乙肝患者(以下简称CHB)的疗效。方法:回顾性收集96例IFN-α经治CHB(IFN-α经治组)接受LMV治疗2—3年生化学、乙肝病毒血清学和病毒学资料,并以同期102例LMV初治患者(LMV初治组)作为对照组,比较既往INF-α治疗对后续LMV疗效的影响。结果:IFN-α经治组在12,24和36月的累积联合应答率分别为26.0%,46.9%和66.0%,而LMV初治组分别为12.8%,25.5%和44.9%,两组之间比较,其差异有统计学意义(P<0.01);在治疗24和36月时,LMV初治组累积病毒学突破率分别为13.7%和26.1%,而IFN-α经治组分别为7.3%和9.6%,两组间比较,其差异有统计学意义(P<0.01);经多因素分析显示IFN-α经治组与3年LMV治疗的联合应答有密切相关性(P<0.01),与HBV-DNA突破也有密切相关性(P<0.05)。结论:LMV对IFN-α经治组HBeAg阳性CHB的抗病毒疗效均显著优于LMV初治组患者,提示既往IFN-α治疗有利于提高LMV的抗病毒应答。

α-2-HS-glycoprotein is a potential marker predicting hepatitis B e antigen seroconversion in patients with chronic hepatitis B during treatment with pegylated interferon alfa-2b

The efficacy of interferon (IFN) is limited in about 1/3 of patients with chronic hepatitis B (CHB). We used two-dimensional electrophoresis (2-DE)-based proteomic strategies to identify potential serum markers predicting hepatitis B e antigen (HBeAg) seroconversion in these patients during IFN therapy. Two groups of patients were enrolled: training and validation. In the training group, 2-DE experiments and subsequent identification of altered levels of proteins showed that α-2-HS-glycoprotein, leucine-rich α-2-glycoprotein, and haptoglobin were significantly upregulated as compared with baseline levels in the HBeAg seroconversion group, whereas apolipoprotein C-III precursor, leucine-rich α-2-glycoprotein, and α-albumin were downregulated in the non-seroconversion group. For patients with HBeAg seroconversion in the training group, Western blot analyses showed that α-2-HS-glycoprotein levels in 75% of patients were significantly upregulated at the end of the treatment as compared with baseline levels. Subsequent experiments in the validation group showed that α-2-HS-glycoprotein levels were significantly increased at week 4 in 83.33% of patients in the HBeAg seroconversion group. Dynamic changes in the serum level of α-2-HS-glycoprotein may be a potential early marker for predicting HBeAg seroconversion during IFN treatment for CHB.

拉米夫定联合α干扰素治疗HBeAg阳性慢性乙型肝炎

目的 :观察拉米夫定和干扰素联合治疗HBeAg阳性慢性乙型肝炎的疗效及其影响因素。方法 :64例HBeAg阳性的慢性乙型肝炎患者随机分成治疗组和对照组。治疗组32例 ,同时使用α干扰素及拉米夫定9个月 ,随后单用拉米夫定15个月,对照组32例 ,单用拉米夫定24个月 ,定期检测丙氨酸转氨酶 (ALT)、HBeAg、抗 -HBe、HBVDNA ,并作YMDD变异检测 ,两组在治疗结束时进行疗效评价。结果 :治疗组ALT复常率为90.6 % (29/32) ,对照组ALT复常率为87.5 % (28/32) ,两组差异无显著性 (P>0.05),治疗组HBeAg阴转率为68.8 % (22/32) ,对照组HBeAg阴转率为37.5 % (12/32) ,两组比较差异有显著性 (P<0.05) ,治疗组HBeAg/抗 -HBe血清转换率为53.1 % (17/32) ,对照组HBeAg/抗 -HBe血清转换率为25 % (8/32) ,两组比较差异有显著性 (P<0.05),治疗组HBVDNA阴转率为78.1 % (25/32) ,对照组HBVDNA阴转率为59.4 % (19/32) ,两组比较差异无显著性 (P>0.05) ,治疗组YMDD变异率为21.9 % (7/32) ,对照组YMDD变异率为40.6 % (13/32) ,两组比较差异无显著性 (P>0.05) ,同时治疗组ALT复常率、HBeAg转换率、HBVDNA阴转率与治疗前ALT及HBVDNA基线水平有关。结论 :α干扰素联合拉米夫定治疗HBeAg阳性的慢性乙型肝炎对于ALT中度升高、HBVDNA高水平复制?

α-干扰素联合拉米夫定治疗慢性乙型肝炎的Th1/Th2应答

目的了解α-干扰素和拉米夫定联合治疗慢性乙型肝炎的短期效果,以及对两种辅助性T细胞(Th1/Th2)细胞因子的表达水平的影响。方法71例HbeAg阳性的慢性乙型肝炎患者随机分成治疗组与对照组。治疗组34例,同时使用α-干扰素和拉米夫定26周,随后单用拉米夫定26周;对照组37例,单用拉米夫定52周。观察其血清生化指标、病毒复制指标及外周血淋巴(PBMC)培养上清液的IFN-γ、IL-4水平。结果两组完全应答率无显著性差异(p=0.08)。两组在治疗3个月时IFN-γ水平均有明显上升(p=0.02,0.01),在治疗6个月时对照组IFN-γ水平明显下降(p=0.03),低于治疗组(p=0.04)。治疗组IL-4水平在第3、6个月明显降低(p=0.01,0.02),而对照组IL-4水平虽有所下降,但差异无统计学意义(p=0.23,0.09)。组间比较发现,两组治疗前、治疗3个月、6个月IL-4水平无差别(p=0.18,0.58,0.14)。结论α-干扰素与拉米夫定联合用药与单用拉米夫定短期疗效并无显著性差异,但联合用药所诱导机体产生的HBV特异性CTL反应较单用拉米夫定更强且持久,提示两组的远期疗效可能会出现差异。

拉米夫定并干扰素α对HBeAg阳性慢性乙型肝炎效果

目的评价拉米夫定（LMD）并干扰素α（IFNα）治疗HBeAg阳性慢性乙型肝炎（CHB）的效果。方法将160例HBV-DNA和HBeAg阳性的CHB病人随机分为A、B、C共3组。A组给予LMD 100 mg/d,联用IFNα5 MU,3次/周;B组单用LMD 100 mg/d;C组单用IFNα5 MU,3次/周,3组均12个月为一疗程。3组均在6个月及疗程结束时进行疗效评价。结果治疗6个月时,A组HBeAg转阴率、HBeAg/抗-HBe血清转换率均显著高于B组,差异有显著性（χ2=9.646、11.332,P〈0.05）;A组丙氨酸氨基转移酶（ALT）复常率显著高于C组,差异有显著性（χ2=24.158,P〈0.05）。疗程结束时,A组HBeAg转阴率、HBeAg/抗-HBe血清转换率均显著高于B组,差异有显著意义（χ2=15.684、13.907,P〈0.05）,A组酪氨酸-蛋氨酸-天门冬氨酸-天门冬氨酸（YMDD）变异率明显低于B组,差异有显著意义（χ2=5.688,P〈0.05）;A组ALT复常率、HBV-DNA转阴率、HBeAg转阴率、HBeAg/抗-HBe血清转换率均明显高于C组,差异有显著意义（χ2=5.649~7.016,P〈0.05）。结论 LMD联合IFNα是HBeAg阳性CHB病人安全而较有效的治疗方法,其YMDD变异率低于单用LMD,疗效明显优于单用LMD或IFNα。

Frequency ofT-cell FoxP3＋ Treg and CD4＋/CD8＋ PD-1 expression is related to HBeAg seroconversion in hepatitis B patients on pegylated interferon

Background Host immune responses against hepatitis B virus （HBV） induced by antiviral therapy play a crucial role in viral clearance. To further investigate the immune mechanisms underlying the differences between respondents and non-respondents, we analyzed myeloid dendritic cells （mDCs）, plasmacytoid dendritic cells （pDCs）, FoxP3＋ regulatory T cells （FoxP3＋ Treg） and programmed death 1 （PD-1） expression in CD4＋/CD8＋ T cells in chronic hepatitis B patients undergoing pegylated interferon （PeglFN）α-2b treatment. Methods Patients received PeglFNα-2b for 24 or 48 weeks, with follow-up at 24 weeks. The frequencies of mDCs, pDCs, FoxP3＋ Treg, and PD-1 expression by CD4＋/CD8＋ T cells were evaluated by flow cytometry at baseline, weeks 4 and 12, end of treatment, and follow-up （12/24 weeks）. Results In HBeAg seroconverters （respondents）, the mDC relative frequency decreased at week 4 and then rebounded at week 12. The pDC relative frequency decreased consistently. In non-HBeAg seroconverters （non-respondents）, both mDC and pDC frequencies decreased slightly. The FoxP3＋ Treg relative frequency decreased during treatment and remained low during follow-up in respondents, while in non-respondents it decreased slightly during therapy but rebounded after discontinuation. In patients with HBeAg 〈17.55 PEI-U/ml at week 12 and 〈8.52 PEI-U/ml at week 24, the FoxP3＋ Treg frequency decreased during treatment and at follow-up. In respondents, CD4~PD-1 and CD8＋PD-1 levels decreased at week 4 and remained low at week 12. In non-respondents, PD-1 expression decreased at week 4 but rebounded at week 12. Conclusions The results indicate that the dynamic changes in DCs, FoxP3＋ Treg frequency, and PD-1 expression by CD4＋ and CD8＋ T cells exhibit different trends in HBeAg and non-HBeAg seroconversion patients. During PeglFNa-2b treatment of chronic hepatitis B patients, these changes may be of predictive value for HBeAg seroconversion. HBsAg and HBeAg levels are related to FoxP3＋ Treg frequency.

聚乙二醇干扰素α-2a联合恩替卡韦治疗拉米夫定耐药的慢性乙型肝炎患者疗效分析

目的探讨聚乙二醇干扰素α-2a联合恩替卡韦治疗拉米夫定耐药的HBe Ag阳性慢性乙型肝炎患者的疗效。方法随机将85例拉米夫定耐药患者分为两组,给予45例CHB患者恩替卡韦治疗,40例患者接受恩替卡韦和聚乙二醇干扰素α-2a治疗。结果在治疗24 w末,两组血清ALT和AST水平均较治疗前下降,在治疗48 w末,联合组血清ALT和AST水平较恩替卡韦治疗组显著降低,差异有统计学意义(P<0.05);联合组血清HBe Ag阴转和血清转换率均显著高于恩替卡韦治疗组(P<0.05)。结论应用聚乙二醇干扰素α-2a联合恩替卡韦治疗拉米夫定耐药的HBe Ag慢性乙型肝炎患者可提高HBe Ag转阴率和血清转换率,治疗安全。

聚乙二醇干扰素α-2a联合短程拉米夫定治疗HBeAg阳性慢性乙型肝炎的疗效

目的 探讨通过短程联合拉米夫定以提高聚乙二醇干扰素α-2a 疗效的新治疗方法.方法 所有患者以聚乙二醇干扰素α-2a 135μg开始治疗,在治疗12周时,若HBV DNA或HBeAg转阴,继续单独使用干扰素治疗至52周（A组）,未达到上述条件者（B组）分为B1组及B2组,B1组短程联合拉米夫定治疗12周后继续干扰素治疗并完成52周疗程,B2组继续单独用干扰素治疗并完成52周疗程.符合正态分布的计量资料采用t检验 符合偏态分布的计量资料用中位数（全距）表示,采用秩和检验.结果共有58例患者入组,8例患者在治疗12周时出现HBV DNA或HBeAg转阴,单用干扰素完成52周疗程,治疗结束时HBV DNA转阴率、HBeAg血清学转换率,HBsAg转阴率及ALT复常率分别为8/8、6/8、0/8及8/8.B1组患者24例,治疗52周时HBV DNA转阴率、HBeAg血清学转换率,HBsAg转阴率及ALT复常率分别为50%（12/24）、38%（9/24）、4%（1/24）及63%（15/24） B2组患者26例,治疗52周时HBV DNA转阴率、HBeAg血清学转换率,HBsAg转阴率及ALT复常率分别为31%（8/26）、27%（7/26）、O（0/26）及35%（9/26）.结论 聚乙二醇干扰素α-2a治疗取得早期应答的患者治疗52周的应答率高 通过对早期疗效不佳的患者短程联合拉米夫定治疗,可提高干扰素的疗效,但有待更大样本量的随机临床试验证实.

拉米夫定联合白细胞介素2治疗慢性乙型肝炎的疗效观察

目的评价拉米夫定联合白细胞介素2治疗慢性乙型肝炎的疗效和安全性。方法将97例患者随机分为观察组(拉米夫定联合白细胞介素2)和对照组(单用拉米夫定)。拉米夫定疗程至少12个月。观察组联合白细胞介素2,时间为6个月。其中,观察组50例,对照组47例,观察期24个月。结果6个月时,观察组与对照组ALT的复常率分别为82.0%和68.1%(P>0.05);12个月时分别为90.0%和70.2%(P<0.05)。6个月时两组H BeAg阴转率、H BeAg/抗H Be的血清转换率和H BV D N A阴转率差异无显著性(P>0.05);12个月时,两组H BeAg阴转率和H BeA g/抗H Be的血清转换率差异仍无显著性(P>0.05),但观察组H BV D N A阴转率(92.0%)显著高于对照组(70.2%)(P<0.05)。至24个月时,观察组患者血清A LT复常率、H BV D N A阴转率、H BeAg阴转率均显著高于对照组患者(P均<0.05)。用药12个月、24个月时两组H BV Y M D D阳性率相比差异均无显著性(P>0.05)。结论拉米夫定联合白细胞介素2治疗C H B安全有效,优于单用拉米夫定。