Treatment of chronic hepatitis B with the combination of pegylated interferon with lamivudine

Several agents are currently approved for the treatment of chronic hepatitis B: interferon alpha (IFN), pegylated interferon-α (PEG IFN), lamivudine, adefovir, and entecavir. Each agent has inherent limitations. IFN is effective in a minority of patients and has frequent side effects that limit its tolerability. Large randomized controlled trials have demonstrated the efficacy of PEG IFN in the treatment of chronic hepatitis B. The efficacy of lamivudine is limited by the emergence of drug-resistant hepatitis B virus (HBV) mutants, restricting its utility as a long-term therapy. Adefovir is well tolerated and is associated with low incidence of resistance, but its antiviral effect is not optimal. Entecavir has a high antiviral effect and is well tolerated. However, its long term efficacy and resistance profile are not yet determined. Lamivudine, adefovir and entecavir have the advantages of oral administration and excellent safety profiles. However, theyinduce a sustained response after withdrawal of therapy in only a minority of patients, and therefore, the treatment needs to be indefinitely administered in most patients. IFNs have two mechanisms of action: (i) direct antiviral effect by inhibiting synthesis of viral DNA and by activating antiviral enzymes; and (ii) exaggeration of the cellular immune response against hepatocytes infected with HBV. PEG IFN, administered for 48 weeks, gives an overall sustained response rate of approximately 30%. Two large randomized controlled trials have conducted to registration of PEG IFN-α-2a in the treatment of chronic hepatitis B.     

Three-phase sequential combined treatment with lamivudine and interferon in young patients with chronic hepatitis B

Alpha-interferon (IFN) or lamivudine monotherapy are ineffective in treating chronic HBeAg positive patients with high viral load and low alanine aminotransferase (ALT) levels. We investigated whether priming lamivudine treatment might enhance the antiviral and immunostimulant action of lamivudine/IFN combination in young tolerant patients. Eleven chronic HBeAg positive patients received: 100 mg/day lamivudine for 3 months followed by IFN 5 MU/m2/tiw with lamivudine 100 mg/day for 6 months and then lamivudine alone 100 mg/day for 9 months. Quantitative hepatitis B virus (HBV)-DNA was evaluated during treatment and core-promoter, precore and polymerase HBV mutants were detected by direct sequencing at the end of therapy. Serum HBV-DNA levels dropped during lamivudine monotherapy and in combination with IFN. After IFN withdrawal, viraemia transiently increased to high levels in five of 11 (45%) patients who showed rt M204V/I lamivudine mutant resistant. Two patients cleared HBeAg without anti-HBe seroconversion. One patient presented core-promoter (A1762T/G1764A) and precore stop codon mutations. Hence, three-phase sequential combined lamivudine/IFN treatment reduced HBV-DNA serum level, but did not lead to HBeAg and HBV-DNA clearance in these highly viraemic, normal ALT patients. Lamivudine/IFN combination did not prevent the emergence of YMDD lamivudine resistance. New schedules of antiviral treatments must be evaluated in this population at risk of disease progression.     

Treatment of chronic delta hepatitis with lamivudine vs lamivudine + interferon vs interferon

Summary.  Chronic delta hepatitis is the most severe form of chronic viral hepatitis for which interferon (IFN) is the only available treatment. In 39 patients (25 were treatment-naïve, 14 had previously used IFN), efficacy of 1-year treatment with IFN (9 MU, t.i.w.) or lamivudine (LAM; 100 mg, q.d.) alone was compared with IFN and LAM combination (2 months of LAM to be followed by combination treatment). IFN monotherapy was given only to treatment-naïve patients. In both treatment-naïve and previous IFN users, end of treatment virological and biochemical responses were similar with IFN–LAM combination and superior to LAM monotherapy ( P  < 0.05). Improvement in liver histology occurred more often with IFN ± LAM than with LAM alone ( P  < 0.05). In treatment-naïve patients, combination treatment was not superior to IFN monotherapy. After treatment discontinuation, virological and biochemical response rates decreased in LAM and IFN combination and IFN monotherapy. On treatment virological response at month 6 of treatment predicted sustained virological response. The results of this study suggest that addition of LAM to IFN for the treatment of delta hepatitis is of no additional value and that both treatment modalities are superior to LAM monotherapy.     

慢性乙型肝炎治疗过程中病毒基因变异及临床意义的研究

目的研究干扰素和拉米夫定治疗慢性乙型肝炎HBV前C区A83点突变及YMDD变异的发生情况,并探讨联合治疗对慢性HBV基因变异的影响.方法90例慢性乙型肝炎病人进行随机化分组,30例肌肉注射干扰素,30例常规口服拉米夫定100 mg/d,30例给予拉米夫定和干扰素联合治疗.治疗前检测血清丙氨酸转移酶水平,HBV DNA滴度(定量)水平,前C区A83点突变和YMDD变异,治疗后第1、3、6、9个月分别进行肝功能、HBV DNA定量检测,应用错配聚合酶链反应及限制性片断长度多态性(mPCR-RFLP)检测HBV基因变异的发生情况,对干扰素治疗、拉米夫定治疗和联合治疗后的慢性HBV变异情况进行比较,进行统计学分析.结果干扰素和拉米夫定治疗慢性乙型肝炎都可引起前C区A83点突变和YMDD变异,干扰素引起的变异以前C区A83突变为主,拉米夫定引起的变异以YMDD变异为主,而联合治疗则较少引起HBV变异,差异有统计学意义(P＜0.05).结论HBV变异是药物治疗选择的结果,干扰素、拉米夫定治疗后使变异株成为优势毒株,药效下降,病毒DNA滴度反跳,拉米夫定联合干扰素治疗HBV,基因变异机会则相对较少.     

Lamivudine/pegylated interferon alfa-2b sequential combination therapy compared with lamivudine monotherapy in HBeAg-negative chronic hepatitis B

BACKGROUND AND AIM: Monotherapy has been proven insufficient in achieving sustained control of chronic hepatitis B. We aimed to assess the efficacy of combined sequential administration of lamivudine and pegylated interferon alfa-2b in patients with hepatitis Be antigen (HBeAg)-negative chronic hepatitis B. METHODS: Eighteen patients were given sequential combination treatment starting with 3 months of lamivudine monotherapy followed by 9 months of pegylated interferon alfa-2b (after a 3-month period of concomitant administration of the two drugs) and 24 patients received lamivudine monotherapy. RESULTS: At the end of treatment, 88.9% of the patients who received sequential combination treatment and 70.8% of those who received lamivudine monotherapy had hepatitis B virus (HBV) DNA levels below 400 copies/mL (P = not significant). At the end of treatment, 72.2% of the patients who received sequential combination treatment and 70.8% of those who received lamivudine monotherapy achieved alanine aminotransferase normalization (P = not significant). After 12 months of follow up, 33.3% of the patients who received sequential combination treatment and 16.7% of those who received lamivudine monotherapy had HBV-DNA levels below 400 copies/mL (P = 0.4). After 12 months of follow up, 72.2% of the patients who received sequential combination treatment and 25.0% of those who received lamivudine monotherapy had normal alanine aminotransferase levels (P < 0.01). Twenty-five percent of the patients in the lamivudine monotherapy group had virological breakthrough compared to none in the sequential combination treatment group (P = 0.06). CONCLUSIONS: Sequential combination treatment is able to improve sustained biochemical response rates and prevent the emergence of lamivudine-resistant mutants in patients with HBeAg-negative chronic hepatitis B.     

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。     

拉米夫定治疗慢性重型肝炎疗效观察

将45例慢性重型乙型肝炎患者随机分为治疗组22例、对照组23例.治疗组在综合保肝治疗的基础上口服拉米夫定100mg、每日1次,对照组仅用综合保肝治疗,疗程均为1年;观察症状、体征、肝功能、血清HBVM和HBVDNA的变化.结果显示,治疗后两组患者症状体征均有一定程度的改善;治疗结束时,治疗组治愈好转率(95.45%)高于对照组(73.91%),病死率(4.5%)低于对照组(17.39%),P均＜0.05.治疗前治疗组13例HBVDNA阴性、9例阳性(650.47±597.22fg/ml),治疗后阴性者持续阴性,阳性者均逐渐转阴;对照组15例HBVDNA阴性、8例阳性(579.52±542.86fg/ml),治疗后阴性者6例阳转,阳性者持续阳性.治疗3个月时,治疗组ALT复常率高于对照组;治疗8个月后治疗组复发率4.7%(1/21),对照组为57.14%(8/14),P＜0.01.提示拉米夫定治疗慢性重型乙型肝炎可使病毒持久转阴,复发率和病死率低.     

拉米夫定和干扰素序贯疗法治疗慢性乙型肝炎的疗效观察

目的我们设计拉米夫定和IFN-α序贯疗法,治疗慢性乙型肝炎患者。方法治疗组28例患者。平均年龄40岁,对照组28例患者,平均年龄40岁。治疗组单用拉米夫定100mG/d 20周,而后联合IFN-α2b 5Mu tiw和拉米夫定4周。最后单用IFN-α24周。结果 拉米夫定治疗结束时,全部血清HBVDNA转阴;序贯治疗结束后6个月,血清HBVDNA持续阴性16/28,HBeAg转为抗-HBe 10/28,HBeAg和HBsAg均出现血清学转换6/28,全部应答患者ALT复常。结论 本临床研究结果表明,拉米夫定和IFN-α序贯疗法治疗慢性乙型肝炎患者可诱导包括抗-HBs血清学转换的持续应答,此治疗方案值得在临床实践中进一步评价。     

IFN-γ联合拉米夫定治疗慢性乙型肝炎临床观察

目的观察IFN-γ(上生雷泰)联合拉米夫定治疗慢性乙型肝炎的疗效.方法300例患者随机分为3组,每组100例,分别应用上生雷泰 拉米夫定,α-干扰素(赛若金) 拉米夫定,胸腺肽 拉米夫定,治疗18个月后检测ALT复常率、HBeAg阴转率、抗HBe阳转率、HBV DNA(PCR法)阴转率.结果上生雷泰 拉米夫定组ALT复常率75%,HBeAg阴转率38%,抗HBe阳转率30%,HBV DNA阴转率73%;赛若金 拉米夫定组ALT复常率65%,HBeAg阴转率20%,抗HBe阳转率7%,HBV DNA阴转率52%;胸腺肽 拉米夫定组ALT复常率65%,HBeAg阴转率20%,抗HBe阳转率7%,HBV DNA阴转率52%;胸腺肽 拉米夫定组ALT复常率35%,HBeAg阴转率10%,抗HBe阳转率7%,HBV DNA阴转率25%.结论上生雷泰 拉米夫定组疗效优于赛若金 拉米夫定组及胸腺肽 拉米夫定组.经统计学处理,3组疗效有明显的差异.     

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.     

Lamivudine and 24 weeks of lamivudine/interferon combination therapy for hepatitis B e antigen-positive chronic hepatitis B in interferon nonresponders

BACKGROUND/AIMS: Lamivudine is effective in treatment-naive patients with chronic hepatitis B, but its role in interferon nonresponders has not been described. We assessed lamivudine treatment, with or without added interferon, in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who had failed interferon therapy previously. METHODS: Patients were randomized to lamivudine (100 mg) or placebo for 52 weeks or to a 24-week regimen of lamivudine plus interferon. Primary treatment comparisons were at week 52, with a 16-week posttreatment follow-up period. Measurements included histology (primary endpoint), HBeAg response, normalization of alanine aminotransferase, reduction of hepatitis B virus (HBV) DNA, and safety. RESULTS: Among 238 patients, histologic response was significantly more common in patients treated with lamivudine (52 versus placebo 25%, P=0.002) or the combination regimen (32%, P=0.01). HBeAg loss was also more common with lamivudine (33 versus 13 versus 21%), as were virologic and alanine aminotransferase responses. Among 28 subjects with HBeAg loss/seroconversion, 71% had durable responses 16 weeks posttreatment. CONCLUSIONS: Lamivudine for 52 weeks is as effective in interferon nonresponders as in previously reported treatment-naive patients; however, a combination of lamivudine for 24 weeks and interferon for 16 weeks was not effective in this population.     

Treatment of chronic hepatitis B with recombinant leukocyte interferon and cyanidanol

Twelve male patients with chronic hepatitis B were treated by the combination of recombinant human alpha-interferon and cyanidanol. They received 3 million units of interferon twice a week and 2,250 mg of cyanidanol daily for 24 weeks. Four patients had sustained clinical improvement in which hepatitis B e antigen and DNA polymerase disappeared from sera and aminotransferase activities fell to normal levels. Elevated pretreatment aminotransferases were associated with the response to therapy. Also, decreased number of OKT4-positive cells prior to treatment were observed among responders. Side effects were minimal and all patients tolerated treatment on an outpatient basis. Twice weekly administration of recombinant leukocyte interferon with cyanidanol may be effective in treating chronic hepatitis when patients are appropriately selected.     

Treatment of chronic hepatitis B with recombinant leukocyte interferon and cyanidanol

Twelve male patients with chronic hepatitis B were treated by the combination of recombinant human α-interferon and cyanidanol. They received 3 million units of interferon twice a week and 2,250 mg of cyanidanol daily for 24 weeks. Four patients had sustained clinical improvement in which hepatitis B e antigen and DNA polymerase disappeared from sera and aminotransferase activities fell to normal levels. Elevated pretreatment aminotransferases were associated with the response to therapy. Also, decreased number of OKT4-positive cells prior to treatment were observed among responders. Side effects were minimal and all patients tolerated treatment on an outpatient basis. Twice weekly administration of recombinant leukocyte interferon with cyanidanol may be effective in treating chronic hepatitis when patients are appropriately selected.     

拉米夫定联合干扰素α治疗慢性乙型肝炎疗效观察

目的研究拉米夫定联合干扰素α对慢性乙型肝炎病人的疗效。方法对1999~2001年深圳市东湖医院慢性乙型肝炎病人87例,随机分为2组,观察组36例,用拉米夫定(100mg/d)联合干扰素α(每次5mU)隔日1次肌注,26周后单用拉米夫啶至104周。对照组51例,单用拉米夫啶100mg/d,疗程104周,并评估疗效。结果两组HBVDNA转阴率差异无显著性(P=0.24),联合治疗组的HBeAg/抗-HBe血清转换率高于拉米夫定组(38.9%对17.6%,P=0.03)。联合治疗组的HBVYMDD变异率较低(22.2%对43.1%,P=0.04)。结论联合治疗的2年疗效优于单用拉米夫定,且能减少病毒YMDD变异。     

温阳化瘀汤和拉米夫定序贯治疗慢性乙型肝炎的临床研究

目的:观察温阳化瘀汤和拉米夫定序贯治疗免疫耐受期慢性乙型肝炎患者的临床疗效.方法:60例免疫耐受期慢性乙型肝炎患者随机分为两组,治疗组患者先用温阳化瘀汤水煎取汁,分两次口服,1剂/d;另加服百令胶囊,3次/d,5粒/次.至肝功能ALT＞200U/L后再改为口服拉米夫定,1次/d,100mg/次.对照组患者仅口服拉米夫定,100mg/次,1次/d.口服拉米夫定后观察时间为6个月.观察患者血清肝功能、HBV DNA、Ⅳ-C、HA、LN、PCⅢ等指标的改善情况及治疗前后肝组织病理学的变化.结果:治疗组患者血清ALT有一个先降后升的过程,一般经过3周至3个月可达到正常值上限的5倍以上,并控制在10倍以内,患者阳虚证候明显好转,血清HA水平明显升高,肝脏炎症程度分级均值接近3级,与对照组比较差异有显著性意义(P＜0.001).口服拉米夫定6个月后治疗组患者HBeAg/HBeAb血清转换率、HBV DNA阴转率显著高于对照组;两组患者肝脏炎症程度分级均较服拉米夫定前显著下降,治疗组下降趋势更明显,但组间比较差异无显著性意义;两组患者肝纤维化各项指标检测值有下降趋势,但组间比较差异均无显著性意义.结论:温阳化瘀汤可纠正患者的免疫耐受,温阳化瘀汤联合拉米夫定序贯治疗可提高患者血清HBV标志物的阴转率,增强拉米夫定抗肝纤维化的作用.