重组乙肝疫苗联合干扰素对慢性乙型肝炎患者抗HBV及改善肝功能的临床研究

目的通过重组乙肝疫苗联合干扰素抗HBV研究,探讨其治疗乙型肝炎的可行性及作用机制。方法两组慢性乙型肝炎患者均常规给予保肝降酶药物,联合组每周3次肌注IFNα2b3MU,另加重组乙肝疫苗20μg每月1次三角肌处肌注,疗程为6个月。对照组只单独肌注IFNα2b,分别观察其抗HBV及改善肝功能情况。结果联合组抗HBV及改善肝功能效果与对照组比较有显著差异。结论重组乙肝疫苗联合干扰素抗HBV显示出良好的治疗前景。     

一种新的拉米夫定及干扰素联合疗法抗乙型肝炎病毒的临床研究

目的探讨通过拉米夫定和干扰素单一或联合使用观察其抗病毒效果和对拉米夫定致停药后反跳及治疗中耐药突变的影响,寻找疗效好、费用低的治疗方法. 方法应用前瞻性随机分组方法,对150例未经治疗的乙型肝炎病毒(HBV)患者进行治疗.实验分5组,每组30例,A组(新联合疗法)前3个月使用拉米夫定100 mg/d,第4个月时加用干扰素α,每次3MU,每周3次至疗程结束,但第10个月时将拉米夫定减为100 mg,隔日一次;B组拉米夫定治疗,100 mg/d;C组干扰素α治疗,每次3 MU,每周3次;D组(普通联合疗法)拉米夫定100 mg/d加干扰素α 3MU,每周3次;E组阴性对照组.总疗程均为1 2个月.分别于治疗后第3、6、9、10、11、12个月和随访半年时抽血,并观察各组H BV DNA复制水平、乙型肝炎e抗原(HB eAg)、肝功能及组织学变化,同时应用基因芯片技术,定期监测YMDD突变的情况.结果A组自第3个月即有显著的抗病毒效果,显著高于E组(5例对30例,P＜0.01),直至治疗结束后6个月(10例对29例,P＜0.01),均显示出极好的抑制HBV复制、H BeAg阴转(12例对1例,P＜0.01)和持续的丙氨酸氨基转移酶复常效果[(35.3±11.2)U/L对(85.3±32.2)U/L,P＜0.01].同时,与B组相比,治疗结束后6个月,HBV DNA阳性例数(10例对25例,P＜0.01)及病毒负荷量[(1.02±1.33)×105拷贝/ml对(603.00±89.40)×105拷贝/ml,P＜0.01],差异均有显著性.YMDD突变检出率显著低于B组(x2=4.81,P＜0.05),提示此方案具有显著减少或预防YMDD突变形成的作用.结论新联合疗法具有显著增加抗病毒效果,特别是停药后持续抗病毒疗效.能显著缩短拉米夫定的抗病毒治疗疗程,减少停药后的反跳和病毒耐药性突变的发生,亦能显著降低治疗费用.     

左旋咪唑和干扰素治疗小儿慢性乙型肝炎

为评价同时应用左旋咪唑与IFN对HBV的抗病毒价值,作者对小儿慢性乙型肝炎分两组分别给予IFN或IFN加左旋咪唑,比较其效果,并观察淋巴细胞亚群和血清可溶性白介素-Ⅱ受体(sIL-2R)的变化。 方法:38例患者,年龄3～16岁,平均9.8岁,经组织学证实有慢性肝炎,并存在血清HBV复制标志(HBeAg和HBV DNA)至少持续6月。第Ⅰ组20例单用IFNα-2a,剂量按10MU/m~2,每周用药3次,连     

α干扰素治疗慢性乙型肝炎肝纤维化血清标记与病理评价

目的评价干扰素α(IFN)的抗肝纤维化作用及其抗病毒疗效的关系。方法干扰素α治疗36例慢性乙型肝炎患者,对照组用常规方法治疗,治疗前后检测血清肝纤维化指标HA、PC-Ⅲ、Ⅳ-C、LN以及TGF-β1,B超引导下肝穿作组织学炎症活动度和纤维化程度的评分比较。结果IFN组治疗后HA、PC-Ⅲ、Ⅳ-C、LN和TGF-β1均较治疗前明显降低(P＜0.01),与对照组治疗后相比较,HA、PC-Ⅲ和TGF-β1明显降低(P＜0.05)。IFN组治疗后组织学炎症活动度评分为(9.3±3.2)分降至(6.2±2.1)分,肝纤维化程度评分由(7.5±2.2)分降至(5.1±1.8)分(P值均＜0.05)。结论肝纤维化程度的改善与毒抗病毒疗效密切相关,α干扰素对慢性乙型肝炎肝纤维化有较好疗效。     

抗HBV特异性主动免疫疗法对标准乙型肝炎疫苗免疫无应答者免疫效果分析

目的探讨抗HBV特异性主动免疫疗法对标准重组乙型肝炎(乙肝)疫苗无应答者的免疫效果。方法按0-1-6月方案把472例出生时未接种乙肝疫苗、学龄期常规接种乙肝疫苗无应答者分为2组:主动免疫组106例,为抗HBV主动免疫疗法组,采用乙肝疫苗联合IL-2及MG-CSF行三角肌肌内注射;单用组366例,为单用标准乙肝疫苗注射。结果第一针免疫后7个月,主动免疫组抗HBs的阳性率88.0%,明显高于单用组56.8%(P<0.05);抗HBs滴度主动免疫组为276.7±46.3mIU/ml,明显高于单用组184.6±36.6mIU/ml(P<0.01);免疫后的抗HBs阳性率与家中是否有HBV感染者无关(P<0.05)。结论抗HBV特异性主动免疫对初次免疫无应答者的再次免疫有一定的疗效。     

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＞1×107 copies/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.     

拉米夫定与α干扰素联合治疗慢性乙型肝炎

目的 观察拉米夫定(LAM)联合干扰素α1b(IFNα1b)治疗慢性乙型肝炎的近期疗效和安全性。方法 HBV DNA和HBeAg均阳性的90例慢性乙型肝炎患者，按1：1：1的比例进入三个不同的治疗组。联合治疗组：用IFNα1b 5MU，隔日肌肉注射，及口服LAM 100mg／d，共6个月，随后单用口服LAM 100mg／d6个月；LAM组：口服LAM 100mg／d共12月：IFN组：IFN α1b 5MU，隔日肌肉注射，共6个月。结果 治疗结束时，HBV DNA转阴率，联合治疗组为90．0％，LAM组为80％，IFN组为46．7％。丙氨酸氨基转移酶(ALT)复常率，联合治疗组为90．0％，LAM组为80．0％，IFN组为53．3％。HBeAg／抗HBe血清转换率，联合治疗组为46．7％，LAM组为13．3％，IFN组为33．3％。联合治疗组患者治疗结束时无一例检测到YMDD变异。结论 联合治疗组对HBV DNA抑制作用及ALT复常率高于单用干扰素组，与单用拉米夫定组接近。HBeAg／抗HBe血清转换率高于拉米夫定组，与单用干扰素组相近。初步显示联合治疗组发生YMDD变异较少。     

慢性乙型肝炎抗病毒治疗的浅见

1 乙型肝炎抗病毒治疗的近况 1.1 抗病毒的疗效不能令人满意乙型肝炎病毒(HBV)持续复制是慢性乙型肝炎(CHB)迁延难愈的主要原因,抗HBV治疗是攻克本病的关键。目前国内外公认的抗HBV药物是干扰素-α(IFN-α)     

干扰素-α联合乙型肝炎疫苗治疗慢性乙型肝炎16例

目的:探讨干扰素-α联合乙型肝炎疫苗治疗慢性乙型肝炎的疗效.方法:选择HBv DNA阳性的慢性乙型肝炎32例,分为A、B两组:A组16例接受干扰素-α(赛若金)单独治疗,每次注射干扰素-α5 MU,3次/wk,连续给予6 mo.B组16例接受干扰素-α和乙型肝炎疫苗联合治疗,每次注射干扰素-α 5 MU,3次/wk,连续给予6 mo,另外,干扰素-α注射4 wk和12 wk时注射乙型肝炎蛋白疫苗10μg.治疗前检查ALT与HBv DNA,HBeAg,anti-HBe;治疗开始后每2mo检查1次HBv DNA,ALT,HBeAg,anti-HBe;治疗结束后每3 mo复查HBv DNA,ALT,HBeAg,anti-HBe,共随访6mo.结果:治疗结束后与随访6 mo的结果显示,B组的血清HBv DNA阴转率(分别为37.5%与50.0%)显著高于A组(分别为25.0%与37.5%,P＜0.05);B组血清HBe/抗-HBe转换率(分别为25.0%与37.5%)显著高于A组(分别为12.5%与18.8%,P＜0.05),两组间具有显著差异.结论:干扰素-α联合乙型肝炎疫苗治疗慢性乙型肝炎的抗病毒效果显著优于单独使用干扰素治疗效果.     

慢性乙型肝炎患者抗病毒治疗前后TRECs含量的变化

观察慢性乙型肝炎(CHB)患者经抗病毒治疗前后T细胞受体重排删除环(TRECs)含量的变化。利用实时荧光定量PCR方法检测15例干扰素、13例阿德福韦酯治疗前后的CHB患者及27例健康体检者外周血单个核细胞(PBMCs)中TRECs的含量。CHB患者中TRECs含量为(7.29±2.26)copies/103PBMCs,低于健康体检者TRECs水平(10.48±6.90)copies/103PBMCs,P<0.05;TRECs含量与HBV载量直线相关分析r=0.06,P=0.975;干扰素组治疗后TRECs含量(12.77±5.25)copies/103PBMCs,高于治疗前(7.14±2.69)copies/103PBMCs,P<0.05;阿德福韦酯组治疗后TRECs含量(8.63±3.26)copies/103PBMCs与治疗前(7.46±1.73)copies/103PBMCs比较,P>0.05,差异无统计学意义。CHB患者组中TRECs含量低于正常对照组,TRECs含量与HBV载量无明显相关性,干扰素治疗能提高CHB患者中TRECs的含量,而阿德福韦酯无此作用。     

安络化纤丸联合干扰素α-1b治疗慢性乙型肝炎肝纤维化疗效观察

目的 观察安络化纤丸联合干扰素(interferon,IFN)α-1b(运德素)治疗慢性乙型肝炎(乙肝)肝纤维化的疗效.方法 将129例慢性乙肝肝纤维化患者随机分为安络化纤丸组(AL组)40例、IFN α-1b组(IFN组)43例和安络化纤丸联合IFN α-1b组(AL+IFN组)46例.3组患者在治疗0、24、48周...     

Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed

A significant proportion of human immunodeficiency virus (HIV) infected patients are coinfected with hepatitis B virus (HBV). Currently available treatments for chronic hepatitis B (interferon [IFN]-alpha and lamivudine [3TC]) have limited long-term utility because of side effects or of the development of resistance. Tenofovir disoproxil fumarate (TDF) is a nucleotide analog with excellent activity in vitro against HBV, which is also active against 3TC-resistant HBV variants. In this 24-week pilot study, the anti-HBV activity of TDF was prospectively evaluated in a cohort of 6 HIV coinfected subjects for whom 3TC and IFN therapy had previously failed. At baseline, all patients were taking 3TC or FTC and were hepatitis B surface antigen and hepatitis B e antigen positive; 4 had cirrhosis. Baseline HBV load was 7.95 log(10) copies/mL. By weeks 12 and 24, HBV load had decreased by 3.1 log(10) copies/mL and 4.3 log(10) copies/mL, respectively. There was a transient increase of transaminases after the initiation of treatment. No patient developed HBe antibodies. TDF is a very promising drug for the treatment of chronic hepatitis B in HIV-infected individuals.     

干扰素α-1b联合抗-HBV特异性主动免疫疗法治疗慢性乙型肝炎的临床研究

目的探讨普通干扰素α-1b（IFNα-1b）联合抗HBV特异性主动免疫疗法（SAI）治疗慢性乙型肝炎（CHB）患者的疗效。方法292例诊断为有活动性病毒复制（HBeAg阳性、HBVDNA〉1×10％opies／m1），ALT≥2×ULN）的慢性乙型肝炎患者，随机分为A、B、C、D4组。A组用IFNα-1b加SAI联合治疗；B、C两组分别用IFNα-1b与SAI单一疗法；D组作为对照组用常规保肝治疗。治疗前及治疗后第12月比较各组患者HBVDNA、HBeAg血清学转换及ALT复常，并在大部分患者比较治疗前后肝组织Knodell炎症坏死与Ishak纤维化计分情况。结果在治疗终点，A、B、C、D4组HBVDNA达到测不出水平的百分率分别为64．8％、32．4％、30．8％与2．8％；HBeAg血清转换分别为41．6％、27．0％、16．6％与5．6％；ALT复常率分别为89．2％、70．3％、83．3％与44．4％；Knodell与Ishak计分缓解率分别为45．8％、18．8％、12．9％、0．0％与39．4％、34．4％、30．4％、0．0％。结论IFNα-1b加SAI联合疗法对有活动性病毒复制的慢性乙型肝炎患者的疗效优于IFNα-1b或SAI单一疗法。     

Chronic hepatitis B

Opinion statement Interferon alpha, lamivudine, and adefovir are the three drugs currently approved for the treatment of chronic hepatitis B virus (HBV). There are pros and cons associated with the use of each drug. Individualization of therapy, based upon factors such as patient comorbidities, response to prior therapies, and stage of disease, is recommended. Patients with abnormal liver enzymes, indices of active viral replication (HBV DNA positive ± hepatitis B early antigen [HB_eAg] positive) or evidence of necroinflammatory activity on liver biopsy, and compensated liver disease are potential candidates for treatment with interferon, lamivudine, or adefovir. Patients with abnormal liver enzymes, indices of active viral replication (HBV DNA positive ± HB_eAg positive), and decompensated liver disease are candidates for treatment with lamivudine or adefovir. Consideration of liver transplantation should occur concurrently. Interferon alpha treatment results in hepatitis B surface antigen [HB_eAg] loss and sustained suppression of HBV DNA replication in 30% to 40% of treated patients. Loss of HBsAg occurs in nearly 10% of patients and a higher than expected frequency of HBsAg loss occurs long-term. The main limitation of therapy is the side effects and the need for parenteral administration. Additionally, interferon therapy is not applicable to all patient groups. Lamivudine achieves HB_eAg seroconversion in 15% to 20% of patients treated for 12 months, but (HBsAg) loss is rare. Reduction in HBV DNA to undetectable levels (by hybridization assay) during treatment is nearly universal, and histologic improvement is seen in about 55% of patients. The main limitation of lamivudine therapy is the development of drug resistance, which occurs in 20% of patients after 12 months and increases with duration of therapy (55% at 3 years). Adefovir achieves HB_eAg seroconversion in 12% of patients treated for 12 months, but HBsAg loss is rare. An average 3.5 log reduction in HBV DNA levels is and histologic improvement occurs in 50% to 60% of patients. It is effective against both wild-type and lamivudine-resistant HBV. The risk of drug resistance is low and estimated to be approximately 2% to 3% after 2 years of treatment. Several new antiviral agents are currently under evaluation in clinical trials. In addition, there are two drugs (tenofovir and emtricitabine) that have been approved for HIV infection and that have anti-HBV activity. In the future, combination therapy for chronic HBV infection can be anticipated. Utilization of two or more anti-HBV drugs would be predicted to enhance efficacy and reduce the likelihood of emergence of drug resistance.     

Control of hepatitis B virus replication by interferons and Toll-like receptor signaling pathways

Hepatitis B virus (HBV) infection is one of the major causes of liver diseases, affecting more than 350 million people worldwide. The interferon (IFN)-mediated innate immune responses could restrict HBV replication at the different steps of viral life cycle. Indeed, IFN-α has been successfully used for treatment of patients with chronic hepatitis B. However, the role of the innate immune response in HBV replication and the mechanism of the anti-HBV effect of IFN-α are not completely explored. In this review, we summarized the currently available knowledge about the IFN-mediated anti-HBV effect in the HBV life cycle and the possible effectors downstream the IFN signaling pathway. The antiviral effect of Toll-like receptors (TLRs) in HBV replication is briefly discussed. The strategies exploited by HBV to evade the IFN- and TLR-mediated antiviral actions are summarized.     

Reversal of hepatitis B virus-induced immune tolerance by an immunostimulatory 3p-HBx-siRNAs in a retinoic acid inducible gene I-dependent manner

It is extensively accepted that hepatitis B virus (HBV) escapes from innate immunity by inhibiting type I interferon (IFN) production, but efficient intervention to reverse the immune tolerance is still not achieved. Here, we report that 5'-end triphosphate hepatitis B virus X gene (HBx)-RNAs (3p-HBx-short interfering [si]RNAs) exerted significantly stronger inhibitory effects on HBV replication than regular HBx-siRNAs in stably HBV-expressing hepatoplastoma HepG2.2.15 cells through extremely higher expression of type I IFNs, IFN-induced genes and proinflammatory cytokines, and retinoic acid inducible gene I (RIG-I) activation. Also, 3p-HBx-siRNA were more efficient to stimulate type I IFN response than HBx sequence-unrelated 3p-scramble-siRNA in HepG2.2.15 cells, indicating that a stronger immune-stimulating effect may partly result from the reversal of immune tolerance through decreasing HBV load. In RIG-I-overexpressed HepG2.2.15 cells, 3p-HBx-siRNAs exerted stronger inhibitory effects on HBV replication with greater production of type I IFNs; on the contrary, in RIG-I-silenced HepG2.2.15 cells or after blockade of IFN receptor by monoclonal antibody, inhibitory effect of 3p-HBx-siRNAs on HBV replication was largely attenuated, indicating that immunostimulatory function of 3p-HBx-siRNAs was RIG-I and type I IFN dependent. Moreover, in HBV-carrier mice, 3p-HBx-siRNA more strongly inhibited HBV replication and promoted IFN production than HBx-siRNA in primary HBV(+) hepatocytes and, therefore, significantly decreased serum hepatitis B surface antigen and increased serum IFN-β. CONCLUSION: 3p-HBx-siRNAs may not only directly inhibit HBV replication, but also stimulate innate immunity against HBV, which are both beneficial for the inversion of HBV-induced immune tolerance.     

Effects of antiviral therapy on preventing liver tumorigenesis and hepatocellular carcinoma recurrence

Chronic hepatitis B virus(HBV)infection is the key driving force of liver disease progression,resulting in the development of hepatic dysfunction,cirrhosis and hepatocellular carcinoma(HCC).The primary aim of therapy is to suppress or eliminate HBV replication to reduce the activity of hepatitis,thus reducing the risk of,or slowing the progression of,liver disease.Nucleos(t)ide analogues(Nucs)may result in rapid suppression of HBV replication with normalization of serum transaminases and restore liver function,thus increasing survival in patients with hepatic decompensation.Long-term Nuc therapy may result in histological improvement or reversal of advanced fibrosis and reduction in disease progression,including the development of HCC.The long-term benefits of a finite course of interferon(IFN)-αtherapy also include a sustained and cumulative response,as well as hepatitis B surface antigen seroclearance and reduction in the development of cirrhosis and/or HCC.Pegylated IFN and newer Nucs may achieve better long-term outcomes because of improved efficacy and a low risk of drug resistance.However,treatment outcomes are still far from satisfactory.Understanding the effects of anti-HBV treatment against HCC incidence and recurrence after hepatectomy or liver transplantation is required for further improvement of outcome.     

In Vivo Modelling of Hepatitis B Virus Subgenotype A1 Replication Using Adeno-Associated Viral Vectors

The paucity of animal models that simulate the replication of the hepatitis B virus (HBV) is an impediment to advancing new anti-viral treatments. The work reported here employed recombinant adeno-associated viruses (AAVs) to model HBV subgenotype A1 and subgenotype D3 replication in vitro and in vivo. Infection with subgenotype A1 is endemic to parts of sub-Saharan Africa, and it is associated with a high risk of hepatocellular carcinoma. Recombinant AAV serotype 2 (AAV2) and 8 (AAV8) vectors bearing greater-than-genome-length sequences of HBV DNA from subgenotype A1 and D3, were produced. Transduced liver-derived cultured cells produced HBV surface antigen and core antigen. Administration of AAV8 carrying HBV subgenotype A1 genome (AAV8-A1) to mice resulted in the sustained production of HBV replication markers over a six-month period, without elevated inflammatory cytokines, expression of interferon response genes or alanine transaminase activity. Markers of replication were generally higher in animals treated with subgenotype D3 genome-bearing AAVs than in those receiving the subgenotype A1-genome-bearing vectors. To validate the use of the AAV8-A1 murine model for anti-HBV drug development, the efficacy of anti-HBV artificial primary-microRNAs was assessed. Significant silencing of HBV markers was observed over a 6-month period after administering AAVs. These data indicate that AAVs conveniently and safely recapitulate the replication of different HBV subgenotypes, and the vectors may be used to assess antivirals’ potency.     

Pediatric issues in new therapies for hepatitis B and C

Two antiviral treatments have been approved for hepatitis B virus (HBV) infection by the US Food and Drug Administration (FDA) for use in children: interferon (IFN)-α, 6 MU/m² three times a week subcutaneously for 6 months, and lamivudine, 3 mg/kg/d orally for 12 months. Twenty-six percent to 58% of children treated with IFN become HBV DNA negative, and up to 38% become negative to hepatitis B e antigen (HBeAg). Lamivudine, a nucleoside analogue that blocks viral replication by inhibition of the HBV polymerase, has been associated with comparable rates of seroconversion of HBeAg to anti-HBe. Loss of surface antigen occurs in less than 5% of patients treated with lamivudine, compared with 3% to 33% in those treated with IFN-α. Fifty percent to 65% of children treated with lamivudine clear HBV DNA after 12 months of therapy, but relapse rates have not been clarified. Patients treated with lamivudine develop drug-resistant (YMDD) mutants in the HBV polymerase at the rate of 16% to 32% per year. No treatments for children with hepatitis C virus (HCV) have been approved by the FDA. However, published reports describe treatment with IFN monotherapy and combination therapy with IFN and ribavirin. Trials of PEG-IFN alone or in combination with ribavirin are in progress. Given the lack of data regarding treatment of HCV in children, it is generally agreed among pediatric hepatologists that the optimal treatment is within the context of randomized, controlled trials.