Μanagement of patients with hepatitis B and C before and after liver and kidney transplantation

New nucleos(t)ide analogues(NAs) with high genetic barrier to hepatitis B virus(HBV) resistance(such as entecavir, tenofovir) have improved the prognosis of patients with HBV decompensated cirrhosis and have prevented HBV recurrence after liver transplantation(LT). NAs are considered the most proper approach for HBV infection in patients under renal replacement therapy but their doses should be adjusted according to the patient's creatinine clearance. In addition, physi-cians should be aware of the potential nephrotoxicity. However, patients with chronic hepatitis C and decom-pensated cirrhosis can receive only one therapeutic option before LT, as well as for Hepatitis C virus(HCV) recurrence after LT, which is the combination of sub-cutaneous Peg-IFN and ribavirin. Generally, therapy for HCV after renal transplantation should be avoided. Although the optimal antiviral therapy for HCV infec-tion has not been established, attention has turned to a new, oral direct acting antiviral treatment which marks a promising strategy in prognosis and in amelioration of these diseases.     

Reactivation of hepatitis B after liver transplantation: Current knowledge,molecular mechanisms and implications in management

Chronic hepatitis B(CHB) is a major global health problem affecting an estimated 350 million people with more than 786000 individuals dying annually due to complications, such as cirrhosis, liver failure and hepatocellular carcinoma(HCC). Liver transplantation(LT) is considered gold standard for treatment of hepatitis B virus(HBV)-related liver failure and HCC. However, post-transplant viral reactivation can be detrimental to allograft function, leading to poor survival. Prophylaxis with high-dose hepatitis B immunoglobulin(HBIG) and anti-viral drugs have achieved remarkable progress in LT by suppressingviral replication and improving long-term survival. The combination of lamivudine(LAM) plus HBIG has been for many years the most widely used. However, life-long HBIG use is both cumbersome and costly, whereas long-term use of LAM results in resistant virus. Recently, in an effort to develop HBIG-free protocols, high potency nucleos(t)ide analogues, such as Entecavir or Tenofovir, have been tried either as monotherapy or in combination with low-dose HBIG with excellent results. Current focus is on novel antiviral targets, especially for covalently closed circular DNA(ccc DNA), in an effort to eradicate HBV infection instead of viral suppression. However, there are several other molecular mechanisms through which HBV may reactivate and need equal attention. The purpose of this review is to address post-LT HBV reactivation, its risk factors, underlying molecular mechanisms, and recent advancements and future of anti-viral therapy.     

Management of hepatitis B virus infection after liver transplantation

Chronic hepatitis B virus(HBV) infection is responsible for up to 30% of cases of liver cirrhosis and up to 53% of cases of hepatocellular carcinoma. Liver transplantation(LT) is the best therapeutic option for patients with end-stage liver failure caused by HBV. The success of transplantation, though, depends on receiving prophylactic treatment against post-transplant viral reactivation. In the absence of prophylaxis, liver transplantation due to chronic hepatitis B(CHB) is associated with high rates of viral recurrence and poor survival. The introduction of treatment with hepatitis B immunoglobulins(HBIG) during the 1990 s and later the incorporation of oral antiviral drugs have improved the prognosis of these patients. Thus, LT for CHB is now a universally accepted option, with an estimated 5 years survival of around 85% vs the 45% survival seen prior to the introduction of HBIG. The combination of lamivudine plus HBIG has for many years been the most widely used prophylactic regimen. However, with the appearance of new more potent oral antiviral agents associated with less resistance(e.g., entecavir and tenofovir) for the treatment of CHB, new prophylactic strategies are being designed, either in combination with HBIG or alone as a monotherapy. These advances have allowed for more personalized prophylaxis based on the individual risk profile of a given patient. In addition, the small pool of donors has required the use of anti-HBc-positive donors(with the resulting possibility of transmitting HBV from these organs), which has been made possible by suitable prophylactic regimens.     

拉米夫定与阿德福韦酯初始联合及48周时优化治疗慢性乙型肝炎

目的 观察拉米夫定(LAM)、阿德福韦酯(ADV)初始联合治疗慢性乙型肝炎104周时的疗效和耐药发生情况. 方法 将慢性乙型肝炎患者174例,分为3组治疗,疗程104周.初始联合治疗组,LAM与ADV联合治疗104周.LAM、ADV治疗组,初始单药治疗,48周时根据病毒学应答情况进行优化治疗,继续单药治疗或两药联合治疗至104周.在0～104周不同时间点,对病毒学、血清学、生物化学等指标分别进行检测.计量资料采用方差分析;计数资料采用x2检验. 结果 初始联合组,在48周、104周时,HBV DNA转阴率分别为84％和95％;与LAM组比较,48周时x2=4.473,P=0.034,104周时x2=5.547,P=0.016;与ADV组比较,48周时x2=14.802,P＜ 0.01,104周时x2=5.547,P=0.001.HBeAg血清学转换率分别为38％和44％;与LAM组比较,48周时x2=4.543,P=0.033,104周时x2=4.438,P=0.035;与ADV组比较,48周时x2=4.035,P=0.045,104周时x2=4.223,P=0.040.与LAM组、ADV组相比,初始联合组HBV DNA阴转率、HBeAg血清学转换率等均具明显差异,P≤0.05或P≤0.01.初始联合组在104周治疗中病毒学突破为零,与LAM组比较具有明显差异,P≤0.01.结论 LAM与ADV初始联合治疗,相比单药或48周后的优化治疗,能取得更好的病毒学应答,更高的HBeAg血清学转换率及更低的HBV耐药发生.     

阿德福韦治疗拉米夫定耐药慢性乙型肝炎患者的耐药率及耐药株进化情况

目的观察阿德福韦单药长期治疗拉米夫定耐药CHB患者的耐药率,以及阿德福韦耐药相关性HBV变异及耐药株的动态变化。方法23例发生YMDD变异的CHB患者停用拉米夫定,口服阿德福韦10mg,1次/d,治疗68～116周,从患者基线和阿德福韦单药治疗后不同时间点的血清中抽提HBV DNA,采用直接PCR产物测序法进行耐药变异分析;对其中1例发生阿德福韦耐药患者的一系列血清进行基因克隆分析其HBV耐药株的进化情况。结果阿德福韦单药治疗48周的耐药率为4.3%;96周的耐药率为10.5%。HBV耐药株进化分析结果显示:阿德福韦单药治疗后,YMDD变异株比例逐渐下降而rtA181S变异株出现并逐渐增多,随着治疗时间的延长,又出现了rtA181S N236T联合变异株。阿德福韦变异株(rtA181S和rtA181S N236T联合变异株)对继起的阿德福韦联合拉米夫定治疗病毒学应答较差,并出现了1例阿德福韦与拉米夫定多药耐药联合变异株(rtM204I rtN236T)。结论拉米夫定耐药的CHB患者,换用阿德福韦单药长期治疗后,耐药率逐渐增加并可选择出多药耐药联合变异株。     

Review of the pharmacological management of hepatitis B viral infection before and after liver transplantation

The progress in treatment against hepatitis B virus(HBV)with the development of effective and well tolerated nucleotide analogues(NAs)has improved the outcome of patients with HBV decompensated cirrhosis and has prevented post-transplant HBV recurrence.This review summarizes updated issues related to the management of patients with HBV infection before and after liver transplantation(LT).A literature search using the PubMed/Medline databases and consensus documents was performed.Pre-transplant therapy has been initially based on lamivudine,but entecavir and tenofovir represent the currently recommended first-line NAs for the treatment of patients with HBV decompensated cirrhosis.After LT,the combination of HBV immunoglobulin(HBIG)and NA is considered as the standard of care for prophylaxis against HBV recurrence.The combination of HBIG and lamivudine is related to higher rates of HBV recurrence,compared to the HBIG and entecavir or tenofovir combination.In HBIG-free prophylactic regimens,entecavir and tenofovir should be the first-line options.The choice of treatment for HBV recurrence depends on prior prophylactic therapy,but entecavir and tenofovir seem to be the most attractive options.Finally,liver grafts from hepatitis B core antibody(anti-HBc)positive donors can be safely used in hepatitis B surface antigen negative,preferentially anti-HBc/anti-hepatitis B surface antibody positive recipients.     

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。     

联合抗病毒对于拉米夫定耐药慢性乙型肝炎的临床意义

目的通过对应用拉米夫定（LAM）耐药的慢性乙型肝炎患者单药和联合抗病毒治疗效果的比较来了解其临床意义。方法将39例应用拉米夫定并经HBVP基因测序和生化、聚合酶链反应（PCR）证实存在耐药的慢性乙型肝炎患者分为两组,一组加用、另一组换用阿德福韦酯（ADV）,通过对两组患者的生化学、病毒学和血清学应答,耐药变异发生情况的观测来比较两组治疗方案的疗效。结果经72周的连续监测,加用ADV在病毒学应答率上优于换用ADV组（P=0.02）,但在HBVDNA下降程度,生化学、血清学应答方面差异无统计学意义,而出现明确耐药变异数量上加用ADV组明显少于换用ADV组,组间比较差异存在统计学意义（P=0.03）。结论对于LAM耐药的慢性乙型肝炎患者联合治疗在提高抗病毒应答率和降低耐药率方面优于换用ADV。     

Response-guided treatment of cirrhotic chronic hepatitis B patients: Multicenter prospective study

AIM: To observe the effect of response-guided add-on therapy with adefovir(ADV) and lamivudine(LAM) in cirrhotic hepatitis B(CHB) patients.METHODS: A total of 100 patients with CHB and cirrhosis were divided into three arms according to hepatitis B virus(HBV) DNA level after 24 wk LAM monotherapy: Arm A(complete response, HBV DNA ≤ 60 IU/m L, n = 49), Arm B(partial response, HBV DNA: 60-2000 IU/m L, n = 31) and Arm C(inadequate response, HBV DNA 2000 IU/m L, n = 20). ADV was added to LAM at week 48 in Arms A and B, but at week 24 in Arm C. Virological response, YMDD mutations, biochemical response, and liver function were evaluated.RESULTS: Comparison of the three arms demonstrated that early complete virologic response at week 24was associated with maintained viral suppression(undetectable rate of HBV DNA at week 144 was 95.96%, 66.67% and 35.29%, respectively, P = 0.000) and reduced YMDD mutations(mutation rate at week 144 was 0%, 3.23% and 15%, respectively, P = 0.015) after 144 wk treatment. For patients who failed to achieve complete virological response at week 24, switching to combination therapy further decreased HBV DNA level by 1 log10 IU/m L. All three arms obtained biochemical benefits including decline of alanine aminotransferase and elevation of albumin. In patients who developed HBV DNA breakthrough for YMDD mutations, ADV add-on therapy did not induce further multiple drug resistance to LAM or ADV.CONCLUSION: Optimized response-guided add-on therapy of ADV and LAM maintains long-term suppression of HBV DNA and improves liver function in CHB patients with compensated liver cirrhosis.     

Favorable outcome of de novo hepatitis B infection after liver transplantation with lamivudine and adefovir therapy

Abstract: De novo hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT) always progresses to chronic hepatitis because of the patients' immunocompromised status, and only a few then acquire hepatitis B surface antigen (HBsAg) seroconversion even with efficient antiviral therapy. Here we reported the case of a liver transplant recipient with de novo HBV infection who had a favorable outcome after lamivudine (LAM) and adefovir dipivoxil (ADV) antiviral therapy. The patient received OLT because of end‐stage primary biliary cirrhosis and was found to have de novo HBV infection 3 months later. She was treated with LAM, and her serum HBV DNA turned undetectable 2 weeks later. However, serum HBV DNA turned detectable again after 9 months of LAM therapy and a YMDD mutation was detected. The addition of ADV was efficient to treat LAM‐resistant HBV. After 3 months of combination therapy, LAM was stopped and ADV monotherapy was continued. HBsAg seroconversion was achieved after an additional 12 months. The prevention and treatment of de novo HBV infection after OLT is discussed.     

拉米夫定耐药后阿德福韦酯治疗应答欠佳患者乙型肝炎病毒耐药变异模式

目的 观察拉米夫定(LAM)耐药后单用或联合阿德福韦酯(ADV)治疗应答欠佳患者HBV耐药变异模式. 方法收集15例LAM耐药后采用ADV治疗病毒学应答欠佳患者的血清,对HBV聚合酶逆转录区进行聚合酶链反应、扩增、克隆、测序,分析与耐药相关的变异模式.组间HBV DNA水平比较采用t检验.结果 单用ADV组检测出A181T+N236T、A181V和A181T 等模式的ADV耐药变异,而联合治疗组中主要检测出M204V+L180M、M204V+L180M+L229V、M204I+L80I和M204V+L180M+V207I等LAM耐药变异模式.另外,在联合治疗组的3份血清中,20%的克隆上同时出现对LAM和恩替卡韦耐药的变异,分别为M204I+L80I+T184I(2/10)、M204V+L180M+T184S(2/10)和M204V+L180M+G173L+S202G(2/10).两组中各有1份未检测出已知耐药变异的血清,在它们的测序结果中发现所有克隆均出现1269L变异,且其中单用组中所有克隆均出现P109S变异.联合治疗组和单用ADV组患者血清HBV DNA水平分别为(3.86±0.85)log10拷贝/ml和(5.71±0.94)log10拷贝/ml,差异有统计学意义(t=3.947,P<0.01).结论 LAM耐药后ADV治疗病毒学应答欠佳的患者中,单用ADV治疗容易筛选出A181T+N236T和A181V/T等ADV耐药变异模式,而联合ADV治疗组仍以M204V+L180M、M204V+L180M+L229V、M204I+L80I和M204V+L180M+V207I等LAM耐药变异模式为主.联合治疗时由于LAM的持续使用可选择出恩替卡韦耐药变异模式T184I/S和S202G;对于部分患者,1269L和P109S变异可能影响ADV治疗应答.     

Virological response to adefovir monotherapy and the risk of adefovir resistance

AIM:To evaluate virological response to adefovir(ADV) monotherapy and emergence of ADV-resistant mutations in lamivudine(LAM)-resistant chronic hepatitis B patients.METHODS:Seventy-seven patients with documented LAM resistance who were treated with 10 mg/d ADV for>96 wk were analyzed for ADV resistance.RESULTS:At week 48 and 96,eight(10%)and 14(18%)of 77 LAM-resistant patients developed the ADV-resistant strain(rtA181V/T and/or rtN236T mutations),respectively.Hepatitis B virus(HBV)DNA levels during therapy ...     

国产阿德福韦酯片治疗拉米夫定失效HBeAg阳性慢性乙型肝炎患者的临床研究

目的评价国产阿德福韦酯片（ADV）10mg／d治疗拉米夫定（LAM）失效的HBeAg阳性慢性乙型肝炎患者的疗效和安全性。方法随机、有限的（12周）双盲、安慰剂对照、多中心临床研究。筛选合格的慢性乙型肝炎患者按照2：1的随机比例,分为ADV＋LAM→ADV组：ADV10mg／d联合LAM100mg／d,治疗12周后改为单用ADV10mg／d治疗36周,共41例;安慰剂＋LAM→ADV组：安慰剂10mg／d联合LAM100mg／d,治疗12周后,改为单用ADV10mg／d,治疗36周,共18例。结果12周双盲治疗结束时,ADV＋LAM→ADV组患者血清中HBV DNA水平与基线相比的平均下降量（2．69lg拷贝／ml）、HBV DNA〈5lg拷贝／ml的患者比例（92．7％）、与基线相比下降≥2lg拷贝／ml的患者比例（78．1％）明显高于安慰剂＋LAM→ADV组（1．06lg拷贝／ml、33．3％、27．8％）,P=0．00。两组患者继续治疗,病毒学、血清学和生化学应答均有进一步改善。两组的不良事件发生率及其种类差异无统计学意义。治疗48周内未发现rtN236T和rtA181V突变。结论ADV10mg／d具有明显抗LAM失效的HBV株复制作用,且随着治疗时间延长作用增强,其安全性与安慰剂相似。     

拉米夫定单药及其初始联合阿德福韦酯治疗失代偿期乙型肝炎肝硬化的疗效比较

目的 比较拉米夫定与阿德福韦酯初始联合或拉米夫定单药治疗失代偿期乙型肝炎肝硬化患者2年的疗效.方法 60例失代偿期乙型肝炎肝硬化接受初始拉米夫定(LAM)与阿德福韦酯(ADV)联合抗病毒治疗,为初始联合组;55例接受拉米夫定(LAM)单药抗病毒治疗,为LAM单药组每1～3个月检测患者肝功能、肾功能、甲胎蛋白、乙型肝炎病毒标志物、血清HBV DNA、凝血酶原时间(PT)、肝脏的超声或CT检查,分别在治疗12个月和24个月时比较疗效.组间均数比较用Mann-Whitney检验,相关性分析时采用Pearson双侧t检验.结果 初始联合组45例治疗12个月时血清HBV DNA阴转率为51.1%(23/45),而40例LAM单药组HBV DNA阴转率为47.5%(19/40);至24个月时,初始联合组HBV DNA阴转率达86.7%(39/45),LAM单药组为60.0%(24/40),两组间差异有统计学意义(P＜0.05).初始联合组治疗24个月时,HBeAg血清学转换率为43.5%(10/23),LAM单药组HBeAg血清学转换率为30.0%(6/20),两组间差异有统计学意义(P＜0.05).ALT复常率在初始联合组治疗12个月时为71.1%(32/45),LAM单药组为65.0%(26/40),至24个月时两组ALT复常率分别为88.9%(40/45)和75.0%(30/40),差异有统计学意义(P＜0.05).初始联合组在治疗12个月和24个月时,分别有4.4%(2/45)和6.7%(3/45)发生病毒学突破,但均未检测到病毒学变异,LAM单药组在12个月和24个月时分别有22.5%(9/40)和37.5%(15/40)发生病毒学突破,并分别有17.5%(7/40)和32.5%(13/40)的患者中检测到病毒学变异,均较联合治疗组高(P＜0.05).初始联合治疗更能改善肝功能,Child-Turcotte-Pugh评分和终末期肝病模型评分亦有更明显下降.随访24个月,LAM和ADV初始联合治疗组累计死亡或肝移植率为16.7%,LAM单药组累计死亡或肝移植发生率为20.0%.两组均未发现有血清肌酐超过正常值上限的病例.结论 LAM与ADV初始联合治疗失代偿期乙型肝炎肝硬化患者能更明显抑制HBV复制,改善肝功能各项指标,降低病死率,值得临床应用.

Abstract：

Objective To compare the efficacy of Lamivudine (LAM) monotherapy and combination therapy with Adefovir Dipivoxil (ADV) for patients with hepatitis B virus (HBV) -related decompensated cirrhosis for 2 years.Methods A total of 115 patients with HBV-related decompensated cirrhosis were erolled in this study,among 60 patients were treated with LAM combined with ADV and 55 were treated with LAM.The liver and kidney functions,HBV DNA,HBV-M,AFP,Ultrasond or CT scan of liver were tested every l-3months.the treatment efficacy was evaluated by month 12 and 24.Results By month 12,the HBVDNA negative rates of combination therapy group and LAM monotherapy group were 51.1% (45 cases) and 47.5% (40 cases) respectively,by month 24 the rates were 86.7% and 60.0% respectively.By month 24 the HBeAg negative rates of combination therapy group and LAM monotherapy group were 43.5% and 30.0%respectively,with significant difference existed between the two therapy groups (P ＜ 0.05).By month 24,the ALT normalization rates of the two groups were 88.9% and 72.5% respectively.Viral breakthrough happened in 2 cases (4.4%) by month 12 and 3 cases (6.7%) by month 24 in LAM and ADV combination group,but no viral resistance observed.Viral breakthrough happened in 9 cases (22.5%) by month 12 and 15 cases (37.5%)by month 24 in LAM monotherapy group with viral resistance observed in 7 cases (17.5%) by month 12 and 13 cases (32.5) by month 24.Significant difference existed between the two groups (P ＜ 0.05).Improvement of liver function was more obviously in the combination group.The accumulative total mortality or liver transplantation rate were 16.7% and 20.0% respectively in combination therapy group and LAM monotheapy group.No renal dysfunction observed in both groups.Conclusion LAM combined with ADV is better choice for patients with HBV-related decompensated cirrhosis as compared to LAM monotherapy.     

Factors contributing to antiviral effect of adefovir dipivoxil therapy added to ongoing lamivudine treatment in patients with lamivudine-resistant chronic hepatitis B

Purpose  The antiviral effect of adefovir dipivoxil (ADV) added to ongoing lamivudine (LAM) treatment for LAM-resistant chronic hepatitis B (CHB) differs among patients. We investigated clinical factors affecting the response to ADV therapy in LAM-resistant CHB. Methods  The subjects were 75 LAM-resistant CHB patients treated with ADV in addition to LAM. Virological response (VR) was defined as HBV DNA clearance (<2.6 logcopies/ml) at 12 months after the start of ADV therapy. Clinical factors contributing to VR were examined by univariate and multivariate analyses. Results  Lower HBV DNA at baseline and negative hepatitis B e antigen (HBeAg) were significant factors affecting VR in univariate analysis. In multivariate analysis, lower HBV DNA at baseline (P = 0.005), negative HBeAg (P = 0.009), and higher ALT (P = 0.036) were significant independent factors contributing to VR. In HBeAg-positive patients, HBV DNA clearance was more frequently observed during ADV therapy in patients with baseline HBV DNA ≤7.0 logcopies/ml than in those with baseline HBV DNA >7.0 logcopies/ml. By contrast, the link of lower HBV DNA at baseline to better therapeutic response was not evident in HBeAg-negative patients. Conclusion  In ADV therapy added to ongoing LAM treatment for LAM-resistant CHB, lower baseline HBV DNA and negative HBeAg contributed to a better antiviral effect. Addition of ADV should be done promptly before marked increase in HBV DNA, especially in CHB patients showing LAM resistance positive for HBeAg.     

Prevention of lamivudine‐resistant hepatitis B recurrence after liver transplantation with entecavir plus tenofovir combination therapy and perioperative hepatitis B immunoglobulin only

T. Karlas, J. Hartmann, A. Weimann, M. Maier, M. Bartels, S. Jonas, J. Mössner, T. Berg, H.L. Tillmann, J. Wiegand. Prevention of lamivudine‐resistant hepatitis B recurrence after liver transplantation with entecavir plus tenofovir combination therapy and perioperative hepatitis B immunoglobulin only.
Transpl Infect Dis 2011: 13: 299–302. All rights reserved Abstract: Combination therapy with antivirals plus hepatitis B immunoglobulin (HBIg) has become the standard treatment for prevention of post‐liver transplant hepatitis B virus (HBV) recurrence. However, HBIg therapy is inconvenient and expensive. Alternative therapeutic approaches with modern nucleos(t)ide analogues are limited so far. The present case report describes prevention of HBV recurrence with entecavir and tenofovir. A 48‐year‐old male patient with hepatitis B‐induced decompensated liver cirrhosis initially improved on lamivudine (LAM) until LAM resistance (rtL180M and rtM204V) emerged followed by renewed decompensation. Therefore, tenofovir was added to LAM leading to undetectable HBV DNA (<200 copies/mL). Six months later, low‐level viremia (479 copies/mL) was detected. Treatment was escalated to tenofovir plus entecavir. HBV DNA became negative again, and the patient underwent orthotopic liver transplantation. HBIg was administered during transplantation (10,000 IU) and on the second and third postoperative days (total dose 26,000 IU). Subsequently, the anti‐hepatitis B surface (HBs) titer rose to 1477 IU/L at day 4 post transplantation. Although HBIg should have been continued, the patient remained on combination therapy with tenofovir plus entecavir only. The anti‐HBs titer decreased and became negative 4 months later. However, under continued combination therapy with oral antivirals, HBV DNA and hepatitis B surface antigen remained negative during the entire follow‐up of 21 months after liver transplantation. Combination therapy with entecavir plus tenofovir may prevent post‐liver transplant hepatitis B recurrence even without HBIg maintenance therapy. This case illustrates that combination oral antiviral therapy might substitute for HBIg as indefinite prophylactic regimen due to profound antiviral efficacy and low risk of viral resistance. Efficacy and safety must be further investigated in randomized controlled trials.     

Combination Therapy in Liver Transplant Recipients with Hepatitis B Virus Without Hepatitis B Immune Globulin

Introduction: Conventional therapy to prevent HBV recurrence in liver transplant (LTx) recipients consists of Hepatitis B Immune Globulin (HBIg). The aim of this review is to investigate the safety and efficacy of converting HBIg and LAM therapy to ADV and LAM therapy. Methods: A retrospective review involving all liver transplant patients with HBV maintained on HBIg and LAM therapy. Results collected included: gender, age, HBV serological and DNA status (COBAS AmpliScreen PCR-based testing). Serologic testing was done every three months. Patients were followed for drug reactions, therapy compliance, and immune suppression compliance. A cost benefit analysis was done for drug comparisons using United States currency values. Results: Patient demographics included: Male (n=6), Female (n=4), mean age 44 years (range 33 to 65). The mean length of follow up since therapy conversion (from HBIg and LMV to ADV and LMV) was 21 months (range 16 to 25 months). Serological status at time of conversion revealed that DNA status remained negative in all patients, HBsAg negative in 10/10, HB eAg (+) (5/10) and HBeAb (+)(5/10). None of the patients experienced an increase in transaminases while on dual ADV and LAM therapy. All patients were maintained on immune suppression monotherapy (tacrolimus) at 7–9 ng/mL. All patients reported compliance with the dual therapy and that they experienced no drug related side effects. Mean yearly costs for ADV and LAM was 7,235.00 United States dollars (range 6,550.00 to 8,225.00); while mean monthly costs for HBIg and LAM; 9225.00 (range 7205.00 to 12005.00). Conclusion: The above results demonstrate beneficial effects of ADV and LAM in place of the current standard of HBIg and LAM therapy. Safety and short term results show nucleoside therapy is adequate at preventing HBV viral recurrence. Lastly, the economic benefit for ADV and LAM vastly outweighed the HBIg and LAM group.     

De novo combination therapy with lamivudine and adefovir dipivoxil in chronic hepatitis B patients

AIM: To investigate the appropriate time for combination therapy in HBeAg positive chronic hepatitis B (CHB) patients with decompensated cirrhosis.METHODS: Thirty HBeAg positive CHB patients with decompensated cirrhosis were enrolled in the study. All of the patients were given 48 wk combination therapy with lamivudine (LAM) and adefovir dipivoxil (ADV). Briefly, 10 patients were given the de novo combination therapy with LAM and ADV, whereas the other 20 patients received ADV in addition to LAM after hepatitis B virus (HBV) genetic mutation.RESULTS: Serum alanine aminotransferase and total bilirubin were both improved in the two groups at 4, 12, 24 and 48 wk after treatment. Serum albumin was also improved at 24 and 48 wk after combination therapy in both groups. The serum HBV DNA level was still detectable in every patient in the two groups at 4 and 12 wk after combination treatment. However, in the de novo combination group, serum HBV DNA levels in 4 (40%) and 9 (90%) patients was decreased to below 1×10³ copies/mL at 24 and 48 wk after the combination treatment, respectively. In parallel, serum HBV DNA levels in 2 (20%) and 8 (40%) patients in the add-on combination group became undetectable at 24 and 48 wk after combination treatment, respectively. Furthermore, 6 (60%) patients in the de novo combination group achieved HBeAg seroconversion after 48 wk treatment, whereas only 4 (20%) patients in the add-on combination group achieved seroconversion. Child-Pugh score of patients in the de novo combination group was better than that of patients in the add-on combination group after 48 wk treatment. Moreover, patients in the de novo combination group had a significantly decreased serum creatinine level and elevated red blood cell counts.CONCLUSION: De novo combination therapy with LAM and ADV was better than add-on combination therapy in terms of Child-Pugh score, virus inhibition and renal function.     

Tenofovir rescue therapy for chronic hepatitis B patients after multiple treatment failures

AIM: To evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) for chronic hepatitis B (CHB) patients after multiple failures.METHODS: A total of 29 CHB patients who had a suboptimal response or developed resistance to two or more previous nucleoside/nucleotide analogue (NA) treatments were included. Study subjects were treated with TDF alone (n = 13) or in combination with lamivudine (LAM, n = 12) or entecavir (ETV, n = 4) for ≥ 6 mo. Complete virologic response (CVR) was defined as an achievement of serum hepatitis B virus (HBV) DNA level ≤ 60 IU/mL by real-time polymerase chain reaction method during treatment. Safety assessment was based on serum creatinine and phosphorus level. Eleven patients had histories of LAM and adefovir dipivoxil (ADV) treatment and 18 patients were exposed to LAM, ADV, and ETV. Twenty-seven patients (93.1%) were hepatitis B e antigen (HBeAg) positive and the mean value of the baseline serum HBV DNA level was 5.5 log IU/mL ± 1.7 log IU/mL. The median treatment duration was 16 mo (range 7 to 29 mo).RESULTS: All the patients had been treated with LAM and developed genotypic and phenotypic resistance to it. Resistance to ADV was present in 7 patients and 10 subjects had a resistance to ETV. One patient had a resistance to both ADV and ETV. The cumulative probabilities of CVR at 12 and 24 mo of TDF containing treatment regimen calculated by the Kaplan Meier method were 86.2% and 96.6%, respectively. Although one patient failed to achieve CVR, serum HBV DNA level decreased by 3.9 log IU/mL from the baseline and the last serum HBV DNA level during treatment was 85 IU/mL, achieving near CVR. No patients in this study showed viral breakthrough or primary non-response during the follow-up period. The cumulative probability of HBeAg clearance in the 27 HBeAg positive patients was 7.4%, 12%, and 27% at 6, 12, and 18 mo of treatment, respectively. Treatment efficacy of TDF containing regimen was not statistically different according to the presence of specific HBV mutations. History of prior exposure to specific antiviral agents did not make a difference to treatment outcome. Treatment efficacy of TDF was not affected by combination therapy with LAM or ETV. No patient developed renal toxicity and no cases of hypophosphatemia associated with TDF therapy were observed. There were no other adverse events related to TDF therapy observed in the study subjects.CONCLUSION: TDF can be an effective and safe rescue therapy in CHB patients after multiple NA therapy failures.     

拉米夫定、阿德福韦酯联合扶正化瘀胶囊治疗乙肝后肝硬化失代偿期的2年疗效观察

目的观察拉米夫定、阿德福韦酯联合扶正化瘀胶囊对于乙肝后肝硬化失代偿期治疗作用。方法将51例乙肝后肝硬化失代偿期患者随机分为两组。对照组(n=21)用常规西药治疗方法,如维生素类和护肝降酶治疗,必要时用人血白蛋白等;治疗组(n=30)给予拉米夫定、阿德福韦酯联合扶正化瘀胶囊,疗程均为2年。观察治疗前后HBV-DNA载量,Child-Pugh评分,透明质酸(HA)、Ⅲ型前胶原肽(PcⅢ)、Ⅳ型胶原(Ⅳ-C)和层黏蛋白(LN)等血清肝纤维化指标,彩色多普勒检查肝脾形态、门静脉内径(Dpv)、脾静脉内径(Dsv)和脾厚度(st)。结果基线时两组以上观察指标均无统计学差异(P>0.05)。治疗结束时,对照组3例死亡(肝癌1例、上消化道出血2例),自身前后对比疗效改善不明显((P>0.05)。治疗组死亡1例(交通意外),自身前后对比观察指标改善优于对照组(P<0.05)。结论拉米夫定、阿德福韦酯联合扶正化瘀胶囊有明显改善乙肝后肝硬化失代偿期Child-Pugh评分作用和肝脾形态,降低HBV DNA水平。