阿德福韦酯治疗对拉米夫定耐药的HBeAg阳性慢性乙型肝炎患者48周临床疗效

目的评价阿德福韦酯治疗对拉米夫定耐药的HBeAg阳性慢性乙型肝炎患者的临床疗效。方法 75例对拉米夫定耐药的HBeAg阳性慢性乙型肝炎患者,联合组（48例）加用阿德福韦酯（10 mg/d）治疗48周;单药组（27例）改用阿德福韦酯（10 mg/d）治疗48周,分别检测治疗前及治疗12周、24周和48周时患者血清HBVDNA定量、HBV血清标志物及肝功能。结果治疗48周时,联合组与单药组HBVDNA阴转率分别为62.5%和29.6%（P〈0.01）,HBeAg阴转率分别为31.3%和11.1%（P〈0.05）,HBeAg血清转换率为16.7%和7.4%（P〉0.05）,ALT复常率分别为91.7%和88.9%（P〉0.05）。治疗48周无肾脏安全性问题发生。结论加用阿德福韦酯可作为对拉米夫定耐药患者治疗的首选方案之一。     

拉米夫定联合阿德福韦酯治疗活动性乙型肝炎肝硬化

目的观察拉米夫定联合阿德福韦酯治疗活动性乙型肝炎肝硬化的临床疗效及安全性和耐药性。方法 48例患者给予拉米夫定联合阿德福韦酯治疗,另48例单用拉米夫定治疗。连续观察96周。结果联合治疗组和对照组96周病死率分别为10.41%（5/48）和22.91%（11/48,P〈0.05）;治疗组在治疗48周、96周后,生化指标改善优于对照组;治疗组Child-Pugh评分比对照组改善明显（P〈0.05）;两组患者并发症发生率有显著性差异（P〈0.05）;治疗组患者HBV DNA转阴率比对照组显著性提高（P〈0.01）;治疗组96周未见耐药发生,而对照组48周和96周有10例和12例发生耐药。结论拉米夫定联合阿德福韦治疗能改善活动性乙型肝炎肝硬化患者肝功能和提高生存率,降低耐药率。     

阿德福韦酯治疗YMDD变异慢性乙型肝炎患者96周疗效观察

目的观察阿德福韦酯联合拉米夫定治疗酪氨酸-蛋氨酸-天门冬氨酸-天门冬氨酸（YMDD）变异感染慢性乙型肝炎患者的疗效。方法选择56例在拉米夫定治疗后发生YMDD变异的慢性乙型肝炎患者,随机分为治疗组28例,给予阿德福韦酯联合拉米夫定治疗;对照组开始治疗与治疗组相同,但在12周后停用拉米夫定,继续服用阿德福韦酯治疗,观察96周的疗效。结果在治疗96周时,两组ALT和HBV DNA水平均显著下降;治疗组HBV DNA转阴率为96.4%,对照组为75.0%（P〈0.05）;治疗组ALT复常率为96.4%,对照组为85.7%（P〉0.05）;两组均未发现与药物相关的不良反应发生。结论阿德福韦酯联合拉米夫定治疗YMDD变异的慢性乙型肝炎患者疗效优于单用阿德福韦酯治疗。     

拉米夫定和阿德福韦酯抗乙型肝炎病毒耐药位点检测及临床意义

目的对应用拉米夫定或阿德福韦酯治疗后耐药的慢性乙型肝炎患者给予联合治疗,观察治疗前后乙型肝炎病毒（HBV）变异模式的变化及对疗效的影响。方法在142例对拉米夫定耐药患者中,给予72例拉米夫定联合阿德福韦酯、70例给予恩替卡韦联合阿德福韦酯冶疗,在72例对阿德福韦酯耐药患者中,给予36例联合拉米夫定、另36例联合恩替卡韦治疗,各组均治疗48 w,测定和比较治疗前后所有患者HBV DNA聚合酶逆转录区相关变异位点变化。结果在拉米夫定初治发生耐药的患者中,发生M204V和IL180M变异率分别为98.6%（140/142）和56.3%（80/142）,接受拉米夫定联合阿德福韦酯治疗患者HBV DNA阴转率为86.1%,与恩替卡韦联合阿德福韦酯治疗患者（97.1%）比,无显著性差异;在阿德福韦酯初治发生耐药的患者中,A181V和N236T变异频率分别为63.9%（46/72）和52.8%（38/72）,接受阿德福韦酯联合拉米夫定治疗患者HBV DNA阴转率为52.8%,显著低于阿德福韦酯联合恩替卡韦组（77.8%,P〈0.05）;在阿德福韦酯联合拉米夫定治疗的36例患者中,19例（52.8%）HBV DNA阴转,在阿德福韦酯联合恩替卡韦治疗的36例患者中,28例（77.8%）患者HBV DNA阴转,差异具有显著性（x2=4.963,P〈0.05）。结论以rtM204变异为主的拉米夫定耐药在联合阿德福韦酯进行挽救治疗后疗效确定;以rtA181变异为主的阿德福韦酯耐药患者在接受阿德福韦酯联合恩替卡韦治疗后的疗效优于联合拉米夫定。     

阿德福韦酯联合拉米夫定治疗慢性乙型肝炎的临床疗效及安全性研究

目的观察阿德福韦酯联合拉米夫定治疗慢性乙型肝炎的安全性及临床疗效。方法 68例CHB患者被分为A组34例,口服阿德福韦酯治疗;B组34例口服阿德福韦酯联合拉米夫定治疗,观察48周。结果治疗12周、24周和48周时,A组和B组患者HBV DNA阴转率分别为5.9%、26.5%、32.4%和61.8%、47.1%、82.4%;HBeAg阴转率分别为5.9%、8.8%、17.6%和20.6%、26.5%、32.4%;血清ALT复常率分别为11.8%3、5.3%、41.2%和73.5%、55.9%、88.2%。结论阿德福韦酯联合拉米夫定治疗慢性乙型肝炎比单用阿德福韦酯具有更好的短期临床疗效。     

加用阿德福韦酯治疗拉米夫定耐药HBeAg阳性慢性乙型肝炎患者的临床疗效

阿德福韦酯是抑制HBV的核苷酸类似物,研究证明其与其他核苷类似物无明显交叉耐药,对拉米夫定耐药患者有很好疗效。本研究通过对34例拉米夫定耐药HBeAg阳性慢性乙型肝炎患者采用拉米夫定加阿德福韦酯联合治疗48周,旨在观察其抗病毒疗效。     

国产阿德福韦酯治疗拉米夫定耐药慢性乙型肝炎的初步疗效观察

目的探讨国产阿德福韦酯治疗拉米夫定耐药慢性乙型肝炎的疗效及安全性。方法采用随机、双盲、双模拟、活性药(拉米夫定)平行对照的研究方法,将发生YMDD变异的慢性乙型肝炎患者作为研究对象,停止原服用的拉米夫定,按1∶1比例,随机接受国产阿德福韦酯10mg联合拉米夫定安慰剂1粒或拉米夫定100mg联合阿德福韦酯安慰剂1粒治疗48周。分别观察两组血清生化学指标、HBVDNA水平、HBV血清学标志物变化以及不良反应的发生率。结果两组各有13例和14例患者分别接受阿德福韦酯和拉米夫定治疗。在治疗48周时,ALT<正常值上限患者的比例在阿德福韦酯组为92.9%(12/13),显著高于拉米夫定组的42.9%(6/14)(P=0.0065);阿德福韦酯组HBVDNAlog10水平下降幅度为(3.562±2.289),拉米夫定组下降为(1.024±2.797),两组组间相比差异有显著性(P<0.05);48周时阿德福韦酯组HBeAg转阴率和血清学转换率皆为23.1%(3/13),而拉米夫定组分别为14.3%(2/14)和7.1(1/14),但两组差异无显著性。结论国产阿德福韦酯治疗拉米夫定耐药慢性乙型肝炎的疗效肯定,安全性好。     

拉米夫定联合阿德福韦酯初始治疗慢性乙型肝炎患者临床观察

目的探讨拉米夫定联合阿德福韦酯初始慢性乙型肝炎的临床疗效。方法将120例慢性乙型肝炎初始患者随机分为两组,分别给予拉米夫定联合阿德福韦酯治疗或拉米夫定单药治疗24周后,对HBV DNA未阴转者再加用阿德福韦酯治疗,观察48周。结果两组HBV DNA总体阴转率无显著性差异（P〉0.05）;对于HBVDNA≥107copies/ml患者,两组HBV DNA阴转率于第4和16周差异无显著性（P〉0.05）,但在第24周（x2=4.573,P〈0.05）和第48周差异具有显著性（x^2=4.289,P〈0.05）。结论对于高病毒载量的慢性乙型肝炎患者宜选用联合方案进行抗病毒初始治疗,以期达到更好的疗效。     

阿德福韦酯联合拉米夫定治疗拉米夫定耐药慢性乙型肝炎的临床观察

目的 观察阿德福韦酯联合拉米夫定治疗拉米夫定耐药慢性乙型肝炎临床疗效.方法 首先在充分告知符合研究对象的患者(80例)病情后根据患者的意愿选择分为:(1)对照组(单药治疗组,n=38例),在拉米夫定应用基础上重叠阿德福韦酯治疗12周后,停用拉米夫定,单独使用阿德福韦酯治疗132周;(2)观察组(联合治疗组,n=42例),出现拉米夫定耐药后联合应用阿德福韦酯144周.每3个月检测患者的HBV-DNA、HBV-M、肝功能、肾功能及血常规等.结果 144周疗程结束后联合治疗组患者HBV-DNA转阴率明显优于对照组,疗效差异有统计学意义(P＜0.01),HbeAg在两组间未见明显差异(P>0.05),联合治疗组治疗后肝功能复常率较单药治疗组高(P<0.05).结论 阿德福韦酯联合拉米夫定治疗拉米夫定耐药慢性乙型肝炎有较好的疗效.     

阿德福韦酯初治与挽救治疗拉米夫定耐药的慢性乙型肝炎观察

目的观察阿德福韦酯初治与拉米夫定治疗耐药后联合阿德福韦酯治疗慢性乙型肝炎患者的疗效。方法将45例入选患者分为两组,其中A组为拉米夫定治疗耐药后加用阿德福韦酯治疗组,B组为阿德福韦酯初治组。治疗前及治疗后12、24、36、48周均检测肝功能、肾功能、HBV DNA载量。结果在治疗12、24周时,A组患者的HBV DNA低于检测下限的比率明显高于B组,差异有统计学意义;治疗48周时,两组HBV DNA载量变化、低于检测下限的比率、ALT复常率的差异均无统计学意义。在治疗期间两组患者的肾功能均正常,均未发现不良反应。结论阿德福韦酯初治与联合拉米夫定治疗拉米夫定耐药后慢性乙型肝炎患者同样有效,值得继续探索。     

乙型肝炎肝衰竭生存者的继续治疗与随访

目的随访α-干扰素、拉米夫定和拉米夫定联合苦参碱防治乙型肝炎肝衰竭生存者的中期疗效。方法在多中心选择亚急性或慢加亚急性乙型肝炎肝衰竭生存者(A组)110例,分别接受α-干扰素、拉米夫定和拉米夫定联合苦参碱治疗6个月;选择慢性乙型肝炎肝衰竭生存者(B组)110例,分别给予拉米夫定和拉米夫定联合苦参碱治疗6个月。随访18个月。结果在随访18个月时,A组患者全部生存,其中25.6%(10/39)接受α-干扰素治疗的患者,改用拉米夫定治疗,21.1%(15/71)接受拉米夫定或拉米夫定联合苦参碱治疗的患者改用阿德福韦酯治疗;B组接受拉米夫定治疗的患者死亡5例(9.4%),接受拉米夫定联合苦参碱治疗的患者死亡6例(10.5%),18.2%(18/99)生存者改用阿德福韦继续治疗。拉米夫定治疗使超过80%患者血清HBVDNA转阴,α-干扰素或拉米夫定联合苦参碱治疗患者HBeAg阴转和HBeAg/抗-HBe血清学转换率不比单用拉米夫定治疗者高。结论乙型肝炎肝衰竭生存者长期口服核苷类抗病毒药对阻断肝纤维化的发展有明显的疗效。由于本组α-干扰素和苦参碱的治疗时间相对较短,其中长期疗效还有待进一步探讨。     

Rapid re-emergence of YMDD mutation of hepatitis B virus with hepatic decompensation after lamivudine retreatment

Lamivudine has a high rate of antiviral resistance. Sequential treatment of anti-hepatitis B virus （HBV） is commonly used for lamivudine resistance. We report 4 cases of patients with rapid redetection of HBV mutants during the lamivudine retreatment. The four patients received lamivudine as an initial treatment of HBV and adefovir and lamivudine as a rescue therapy consecutively. HBV-DNA level, YMDD mutations and adefovir -resistant mutations （RFMP） were tested every 3 mo during the sequential treatment. All the patients showed YMDD mutations during the initial lamivudine therapy. After adefovir therapy for lamivudine resistance, they showed viral breakthrough. Adefovir was switched to lamivudine, however, it did not induce viral suppression at all, rather increased HBV-DNA with rapid reemergence of the YMDD mutations. All the patients had ALT flares, and hepatic decompensation occurred in two patients. After switching to adefovir combined with entecavir or lamivudine for a rescue therapy, the patients had reduction in HBV-DNA and ALT improvement. These cases demonstrated that lamivudine retreatment of patients with preexposed lamivudine resistance leads to rapid reemergence of YMDD mutation with significant viral rebounds and subsequent hepatic decompensation. Sequential administration of lamivudine in patients with a prior history of YMDD mutation should be abandoned.     

Virologic response and resistance to adefovir in patients with chronic hepatitis B

BACKGROUND: The incidence and risk factors for adefovir-resistant HBV have not been clearly defined. AIMS: To characterize the virologic response to adefovir, to determine the rate of adefovir resistance and to explore factors associated with initial virologic response (IVR) and adefovir resistance. METHODS: All hepatitis B patients who received adefovir for > or =6 months at our center were prospectively monitored for virologic response and adefovir resistance. RESULTS: Forty three patients were included; mean treatment duration was 18 months (range 6-45). Thirty four (79%) patients had prior lamivudine. IVR was observed in 44% patients and associated with higher pretreatment ALT (P = 0.05) and the absence of HBeAg (P = 0.02). Six (14%) patients were found to have adefovir-resistant mutations. The cumulative probability of genotypic resistance to adefovir at month 24 was 22%. Patients with adefovir resistance were more likely to have been switched from lamivudine to adefovir monotherapy (P = 0.01), to be older (P = 0.04), and to be infected with HBV genotype D (P = 0.02). CONCLUSIONS: Roughly 50% of patients failed to achieve IVR on adefovir. The cumulative probability of adefovir resistance at 2 years was 22%. Our data suggest that combination of lamivudine and adefovir may prevent emergence of adefovir resistance in patients with lamivudine-resistant HBV.     

Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B

BACKGROUND AND AIMS: Adefovir dipivoxil possesses potent in vitro and in vivo antiviral activity in wild-type hepatitis B. This study assessed the safety and efficacy of adefovir dipivoxil alone and in combination with lamivudine compared with ongoing lamivudine therapy in patients with chronic hepatitis B with compensated liver disease and lamivudine-resistant hepatitis B virus (HBV). METHODS: Fifty-nine hepatitis B e antigen (HBeAg)-positive patients with genotypic evidence of lamivudine-resistant HBV, serum alanine aminotransferase (ALT) level > or =1.2 times the upper limit of normal, and serum HBV DNA level > or =6 log(10) copies/mL despite ongoing treatment with lamivudine were randomized to adefovir dipivoxil 10 mg, lamivudine 100 mg, or addition of adefovir dipivoxil to ongoing lamivudine daily. The primary end point was the time-weighted average change from baseline in serum HBV DNA level (DAVG) up to week 16. RESULTS: Rapid reductions in serum HBV DNA level were seen by 4 weeks in all recipients of adefovir dipivoxil; DAVG(16) was -0.07 in the lamivudine group compared with -2.45 and -2.46 log(10) copies/mL in the adefovir dipivoxil/lamivudine and adefovir dipivoxil monotherapy groups, respectively (P < 0.001). Median change from baseline in serum HBV DNA level at week 48 was 0.0, -3.59, and -4.04 log(10) copies/mL in the lamivudine, adefovir dipivoxil/lamivudine, and adefovir dipivoxil groups, respectively. ALT level normalized in 10 of 19 (53%) and 9 of 18 (47%) recipients of adefovir dipivoxil/lamivudine and adefovir dipivoxil, respectively, compared with 1 of 19 (5%) recipients of lamivudine. Three patients receiving adefovir dipivoxil or adefovir dipivoxil/lamivudine and none receiving lamivudine monotherapy were HBeAg negative at week 48 and one became hepatitis B surface antigen negative. CONCLUSIONS: These data, limited to patients with compensated liver disease, indicate that adefovir dipivoxil alone or in combination with ongoing lamivudine therapy provides effective antiviral therapy in patients with lamivudine-resistant HBV.     

Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus

BACKGROUND AND AIMS: Prolonged lamivudine therapy is associated with treatment-resistant YMDD mutant hepatitis B virus (HBV). We evaluated the efficacy and safety of adding adefovir dipivoxil to lamivudine in 135 patients with chronic hepatitis B (CHB) and YMDD mutant HBV. METHODS: Ninety-five patients with compensated CHB (group A) were randomized to adefovir 10 mg daily (n = 46) or placebo (n = 49) for 52 weeks while continuing treatment with lamivudine. Forty patients with decompensated hepatitis B or post-liver transplantation (group B) received adefovir and lamivudine. The primary end point was a decline in serum HBV DNA level to 10(5) copies/mL or a >2 log(10) reduction from baseline at weeks 48 and 52. RESULTS: HBV DNA response occurred in 85% of patients (39 of 46) in group A given combined therapy versus 11% (5 of 46) receiving lamivudine alone (P < 0.001), with a significant change in HBV DNA level from baseline (P < 0.001) between treatment groups (median, -4.6 vs. +0.3 log(10) copies/mL, respectively). Normalization of alanine aminotransferase levels occurred in 31% of patients (14 of 45) receiving combined therapy versus 6% (3 of 48) receiving lamivudine alone (P = 0.002). Ninety-two percent of patients (36 of 39) in group B had an HBV DNA response (median change of -4.6 log(10) copies/mL) and improved liver chemistries (P < or = 0.001). Both treatment regimens were well tolerated, and renal function abnormalities were not observed in either group. CONCLUSIONS: The addition of adefovir dipivoxil to lamivudine in patients with CHB with compensated or decompensated liver disease due to YMDD mutant HBV is associated with virologic and biochemical improvement during 52 weeks of treatment and is well tolerated.     

Treatment of chronic hepatitis B

Interferon (IFN) alpha, lamivudine, and adefovir are the three antiviral therapies currently approved for the treatment of chronic hepatitis B virus (HBV). Initiation of treatment is indicated in patients with abnormal liver enzymes and markers of active viral replication (ie, HBV DNA positive). Hepatitis B early antigen seroconversion rates are higher and treatment duration is shorter with IFN than with lamivudine or adefovir. However, treatment results in frequent side effects and many patients have contraindications to therapy. Lamivudine and adefovir are better tolerated, but have lower seroconversion rates after 12 months of treatment. Resistance develops in 20% of lamivudine patients after 12 months; adefovir resistance has not been identified to date. Individualization of therapy, based on factors such as patient comorbidities, response to prior therapies, and stage of disease (ie, presence of cirrhosis), is recommended. All patients over the age of 40 or with advanced liver disease should be continually screened for hepatocellular carcinoma with serum alphafetoprotein and abdominal imaging every 6 months.     

Extended treatment with lamivudine and adefovir dipivoxil in chronic hepatitis B patients with lamivudine resistance

Purpose

We and others have reported that adding adefovir dipivoxil (adefovir) to lamivudine results in virological and biochemical improvement in cases of lamivudine resistance. The current study assessed the efficacy and safety of combined therapy after 104 weeks of combined treatment and analyzed the frequency of persistent lamivudine resistant HBV.

Methods

A total of 78 patients with compensated CHB (Group A) were maintained on either adefovir 10 mg daily (n = 38) or placebo (n = 40) while continuing lamivudine. An additional 38 patients with decompensated cirrhosis or post liver transplantation (Group B) received lamivudine plus adefovir. The primary endpoint was HBV DNA response at year 2.

Results

At week 104 of therapy, a significantly greater proportion of patients in Group A on combination therapy (76%) had a decline in serum HBV DNA to ≤10⁵ copies or >2 log₁₀ reduction from baseline compared to those receiving lamivudine alone (13%; p < 0.001). Fifty-two percent of Group A patients on combination treatment continued to have the M204V/I HBV mutation compared to 92% receiving lamivudine alone (p = 0.0013). Virologic response occurred less frequently in patients expressing persistent lamivudine resistant HBV. In Group B, 87% of patients had HBV DNA response at week 104 (median change from baseline of −5.84 log₁₀ copies/mL).

Conclusions

The combination of lamivudine and adefovir for 2 years generally proved effective in lamivudine-resistant cases, but there was a persistently high rate of detection of lamivudine resistant mutants and impaired virologic response in compensated patients.     

Adefovir Dipivoxil Alone or in Combination with Lamivudine for Three Months in Patients with Lamivudine Resistant Compensated Chronic Hepatitis B

We studied clinical and laboratory effects of 3 months of lamivudine with adefovir combination and adefovir dipivoxil (AD) alone in the treatment of patients with lamivudine-resistant hepatitis B virus (HBV) infection. Eligible patients were hepatitis B surface antigen-positive men and women with compensated liver disease who were given lamivudine at least more than 6 months and had HBV polymerase gene mutation. Patients were assigned to receive adefovir 10 mg/day (Group 1) or adefovir 10 mg once daily and lamivudine 100 mg once daily combination during first 3 months, and then stopped lamivudine and continued adefovir (Group 2). Median age was 48 years (34 males and 20 females, and 35 were HBeAg-negative). Baseline median ALT, AST, and HBV DNA levels were 66 IU/l, 49 IU/l, and 6.7 log₁₀ copy/ml, respectively. Median adefovir therapy time and ALT normalization time were 9 and 3.5 months, respectively. There was no significant difference between groups according to the baseline HBV DNA, ALT, HBe Ag status, age, gender, and lamivudine resistance time. Virological and biochemical responses were similar in both groups during therapy. Two patients (8%) had ALT flare more than five times upper limit of normal without any clinical decompensation in Group 1. Mild ALT elevation according to baseline levels were found in 8 (27.6%) and 4 (17.4%) patients, respectively, in Group 2 and Group 1, and no statistically significance between two groups. In conclusion, this study showed that it is not necessary to continue lamivudine therapy while switching to AD therapy. Adefovir alone is effective in the treatment of patients with lamivudine resistant HBV infection and compensated liver disease, without significant clinical and laboratory flares. However, it is not easy to say that switching to AD with cessation of lamivudine is safe, because the study population is not enough for precise conclusion and resistance may be a considerable problem against AD in patients using long-term treatment.     

Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B

BACKGROUND/AIMS: We aimed to evaluate nucleoside/nucleotide combination therapy in treatment-na?ve HBeAg-positive patients with chronic hepatitis B (CHB). METHODS: One hundred and fifteen HBeAg-positive patients received lamivudine 100 mg daily plus placebo (monotherapy) or lamivudine 100 mg plus adefovir dipoxil 10 mg daily (combination therapy) for 104 weeks in a randomized double-blind study. RESULTS: Time-weighted average change in serum HBV DNA from baseline up to week 16 was -4.20 log(10)copies/mL for both groups (p=0.936). At week 104, median serum HBV DNA change from baseline (log(10)copies/mL) for monotherapy and combination therapy was -3.41 versus -5.22, respectively. HBV DNA breakthrough was detected in 44% of monotherapy and 19% of combination therapy patients. The M204V/I mutation was detected in 43% (15/35) and 15% (6/41) of each group, respectively. ALT normalization at week 100 and 104 was 34% (19/56) in the monotherapy group and 45% (23/51) in the combination therapy group (p=0.018). By week 104, HBeAg seroconversion occurred in 20% of monotherapy and 13% of combination therapy patients. Both regimens were well tolerated. CONCLUSIONS: Lower rates of resistance to lamivudine, lower serum HBV DNA levels and higher rates of ALT normalization were seen in the combination therapy group after two years. However, serological outcomes were similar.