Histological outcome for chronic hepatitis B patients treated with entecavir vs lamivudine-based therapy

AIM: To compare the histological outcome of chronic hepatitis B (CHB) patients treated with entecavir (ETV) or lamivudine (LAM)-based therapy.METHODS: We conducted a retrospective analysis of data from 42 CHB patients with advanced fibrosis (baseline Ishak score ≥ 2) or cirrhosis who were treated with ETV or LAM-based therapy in Beilun People’s Hospital, Ningbo between January 2005 and May 2012. The patients enrolled were more than 16 years of age and underwent a minimum of 12 mo of antiviral therapy. We collected data on the baseline characteristics of each patient and obtained paired liver biopsies pre- and post-treatment. The Knodell scoring system and Ishak fibrosis scores were used to evaluate each example. An improvement or worsening of necroinflammation was defined as ≥ 2-point change in the Knodell inflammatory score. The progression or regression of fibrosis was defined as ≥ 1-point change in the Ishak fibrosis score. The continuous variables were compared using t-test or Mann-Whitney test, and the binary variables were compared using χ² test or Fisher’s exact test. The results of paired liver biopsies were compared with a Wilcoxon signed rank test.RESULTS: Nineteen patients were treated with ETV and 23 patients were treated with LAM therapy for a mean duration of 39 and 42 mo, respectively. After long-term antiviral treatment, 94.74% (18/19) of the patients in the ETV arm and 95.65% (22/23) in the LAM arm achieved an HBV DNA level less than 1000 IU/mL. The majority of the patients (94.74% in the ETV arm and 73.91% in the LAM arm) had normalized ALT levels. The median Knodell necroinflammatory score decreased from 11 to 0 in the patients receiving ETV, and the median Knodell score decreased from 9 to 3 in the patients receiving LAM (P = 0.0002 and < 0.0001, respectively). The median Ishak fibrosis score showed a 1-point reduction in ETV-treated patients and a 2-point reduction in LAM-treated patients (P = 0.0019 and 0.0205, respectively). The patients receiving ETV showed a more significant improvement in necroinflammation than the LAM-treated patients (P = 0.0003). However, there was no significant difference in fibrotic improvement between the two arms. Furthermore, two patients in each arm achieved a fibrosis score of 0 post-treatment, which indicates a full reversion of fibrosis after antiviral therapy.CONCLUSION: CHB patients with advanced fibrosis or cirrhosis benefit from antiviral treatment. ETV is superior to LAM therapy in improving necroinflammatory but not fibrotic outcome.     

Recent advances in prevention of hepatitis B recurrence after liver transplantation

Liver transplantation is the only effective treatment for hepatitis B virus(HBV)-related end-stage liver disease.However,without antiviral prophylaxis,the recurrence rate of hepatitis B is as high as 80%-100%,which leads to a 50% mortality rate in the first 2 years after liver transplantation.Combination therapy of hepatitis B immunoglobulin(HBIG) and lamivudine demonstrated a higher efficacy of prophylaxis and further reduced the rate of recurrence to < 10%.The strategy of HBIG combined with lamivudine has been the standard treatment in many centers.However,the high rate of lamivudine resistance and the many disadvantages of HBIG have compelled surgeons to reconsider the longterm efficacy of this strategy for the prevention of HBV reinfection.Recently,new nucleos(t)ide analogues,such as entecavir and tenofovir,have been approved as first-line monotherapies for the treatment of chronic hepatitis B infection.These antiviral medicines have replaced lamivudine as the first choice in the prevention of HBV recurrence after liver transplantation.Various therapies that are composed of entecavir,tenofovir,and lamivudine plus adefovir,with or without HBIG have been adopted in several liver transplant centers.This article reviews the recent advances in prophylaxis for the recurrence of hepatitis B after liver transplantation.     

恩替卡韦治疗慢加急性乙型肝炎肝衰竭疗效的Meta分析

目的 系统评价恩替卡韦治疗慢加急性乙型肝炎肝衰竭的疗效和安全性。方法 应用计算机检索PubMed、Cochrane Library、CBMdisc、CNKI、维普、万方等数据库公开发表的文献,检索年限均从2006年1月至2014年9月。纳入恩替卡韦与拉米夫定相比较治疗慢加急性乙型肝炎肝衰竭的随机对照试验。由两名评判员对纳入试验独立进行质量评价和资料提取,采用RevMan5.1软件进行Meta分析。结果 经筛选共纳入7个随机对照试验,合计823例患者。Meta分析结果显示,恩替卡韦治疗6月以上的患者其病死率显著低于拉米夫定治疗患者[RR=0.75,95%CI（0.60,0.95）,P＜0.05];在治疗2～3 m和6 m以上评价,恩替卡韦治疗患者HBV DNA转阴率也显著高于拉米夫定治疗患者[RR=1.47,95%CI（1.29,1.68）,P＜0.05;RR=1.48,95%CI（1.30,1.67）,P＜0.05],病毒学突破率也显著低于拉米夫定治疗组[RR=0.07,95%CI（0.01,0.54）,P＜0.05],且未出现严重不良反应。结论 恩替卡韦治疗慢加急性乙型肝炎肝衰竭患者的远期病死率和病毒学突破率均显著低于拉米夫定,适合于长期抗病毒治疗。     

恩替卡韦初治慢性乙型肝炎耐药1例报道

<正>恩替卡韦(ETV)自2006年在我国正式上市以来,其抑制HBV作用强且耐药发生率低,因而在慢性乙型肝炎患者中得到广泛应用。目前,国内关于恩替卡韦耐药的报道较少。我们在临床工作中收治1例初治的慢性乙型肝炎患者在抗病毒治疗半年时出现病毒学反弹,并经检测证实发生了恩替卡韦基因型耐药,现报道如下。1病例摘要     

三种核苷类似物治疗肝硬化失代偿期患者的疗效比较

目的观察核苷类药物治疗乙型肝炎肝硬化失代偿期的疗效。方法将83例乙型肝炎肝硬化失代偿期患者随机分为四组。所有患者在保肝、对症治疗的基础上,分别给予拉米夫定(A组)100 mg/d、阿德福韦酯(B组)10 mg/d、恩替卡韦(C组)0.5 mg/d口服,对照组(D组)仅给予保肝、对症治疗。观察所有患者临床症状、体征、肝功能、凝血酶原时间活动度(PTA)、乙型肝炎病毒(HBV)DNA定量、乙型肝炎e抗原(HBeAg)转阴情况等。结果在抗病毒治疗过程中,A组患者死亡2例,另1例在治疗过程中出现YMDD[酪氨酸(Y)、蛋氨酸(M)、2个天冬氨酸(D)]变异及时加用阿德福韦酯退出观察;B组患者死亡1例;C组患者无一例死亡;D组疗效最差,死亡4例。A、B、C组患者临床表现、肝功能及血清病毒学指标均较D组有明显改善,差异有统计学意义(P<0.01)。结论乙型肝炎肝硬化失代偿期患者应给予抗病毒治疗,可首选恩替卡韦,亦可选用阿德福韦酯或拉米夫定。     

A comparison of 48-week treatment efficacy between clevudine and entecavir in treatment-naïve patients with chronic hepatitis B

Purpose  

Clevudine and entecavir are currently available in Korea as antiviral drugs against chronic hepatitis B (CHB). We aimed to compare the efficacy of clevudine and entecavir therapy.     

De novo combination of lamivudine and adefovir versus entecavir monotherapy for the treatment of naïve HBeAg-negative chronic hepatitis B patients

Purpose

Either combination treatment or monotherapy using agents with a high genetic barrier are recommended for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). The aim of this study was to compare effect of naïve HBeAg-negative CHB patients with either de novo combination of lamivudine (LAM) and adefovir dipivoxil (ADV) or entecavir (ETV) monotherapy.

Methods

HBeAg-negative CHB patients (n = 71) with ALT levels between 2 and 10 times the upper normal limit and HBV DNA levels >10⁴ copies/mL were enrolled. Patients were treated with either LAM 100 mg plus ADV 10 mg per day (n = 31) or ETV 0.5 mg per day (n = 40) for 48 weeks.

Results

The average reduction in HBV DNA level compared with baseline were 5.16 ± 1.69 log in the LAM + ADV group and 5.36 ± 1.70 log in the ETV group by week 48 (P = 0.624). The virological response (VR) rates were 80.65 and 77.5%, the biochemical response (BR) rates were 93.55 and 90.00% at week 48 in the LAM + ADV and ETV groups, respectively. There was no significant difference in the VR and BR between the two groups. During the 48-week treatment period, virological breakthrough and serious side effects were not noted in any patient.

Conclusions

Both LAM + ADV combination therapy and ETV monotherapy are effective in naïve HBeAg-negative CHB patients, but further studies are needed to obtain long-term results.     

恩替卡韦治疗慢性乙型肝炎和乙型肝炎肝硬化96周疗效观察

目的探讨恩替卡韦治疗慢性乙型肝炎和乙型肝炎肝硬化96周的临床疗效。方法应用恩替卡韦治疗HBV DNA阳性的34例慢性乙型肝炎患者和24例乙型肝炎肝硬化患者,观察96周。结果 34例慢性乙型肝炎患者治疗12周、24周、48周和96周时HBV DNA低于检测下限比率分别为61.76%（21/34）,82.35%（28/34）,94.12%（32/34）和94.12%（32/34,P〈0.05）;22例乙型肝炎肝硬化患者也分别为72.73%（16/22）,81.82%（18/22）,81.82%（18/22）和90.91%（20/22,P〈0.05）;治疗期间未发生与应用恩替卡韦相关的不良反应。结论恩替卡韦治疗慢性乙型肝炎和乙型肝炎肝硬化患者有明显的疗效,安全性较好。     

Delayed hypersensitivity reaction resulting in maculopapular-type eruption due to entecavir in the treatment of chronic hepatitis B

Several clinical trials have demonstrated the potent antiviral efficacy of entecavir (ETV), and this relatively new nucleoside analogue drug has rapidly become a frequently prescribed therapy for chronic hepatitis B (CHB) worldwide. While the studies have also shown a good overall safety profile for ETV, adverse drug reactions (ADRs) in patients with advanced cirrhosis have been reported and represent a broad spectrum of drug-induced injuries, including lactic acidosis, myalgia, neuropathy, azotemia, hypophosphatemia, muscular weakness, and pancreatitis, as well as immune-mediated responses (i.e., allergic reactions). Cutaneous ADRs associated with ETV are very rare, with only two case reports in the publicly available literature; both of these cases were classified as unspecified hypersensitivity allergic (type I) ADR, but neither were reported as pathologically proven or as evaluated by cytokine release analysis. Here, we report the case of a 45-year-old woman who presented with a generalized maculopapular rash after one week of ETV treatment for lamivudine-resistant CHB. The patient reported having experienced a similar skin eruption during a previous three-month regimen of ETV, for which she had self-discontinued the medication. Histopathological analysis of a skin biopsy showed acanthotic epidermis with focal parakeratosis and a perivascular lymphocytic infiltrate admixed with interstitial eosinophils in the papillary and reticular dermis, consistent with a diagnosis of drug sensitivity. A lymphocyte stimulation test showed significantly enhanced IL-4, indicating a classification of type IVb delayed hypersensitivity. The patient was switched to an adefovir-lamivudine combination regimen and the skin eruption resolved two weeks after the ETV withdrawal. This case represents the first pathologically and immunologically evidenced ETV-induced delayed type hypersensitivity skin reaction reported to date. Physicians should be aware of the potential, although rare, for cutaneous ADRs associated with ETV treatment.     

Hepatitis B and liver transplantation: Molecular and clinical features that influence recurrence and outcome

Hepatitis B virus (HBV) continues to be a major cause of morbidity and mortality worldwide. It is estimated that about 350 million people throughout the world are chronically infected with HBV. Some of these people will develop hepatic cirrhosis with decompensation and/or hepatocellular carcinoma. For such patients, liver transplantation may be the only hope for cure or real improvement in quality and quantity of life. Formerly, due to rapidity of recurrence of HBV infection after liver transplantation, usually rapidly progressive, liver transplantation was considered to be contraindicated. This changed dramatically following the demonstration that hepatitis B immune globulin (HBIG), could prevent recurrent HBV infection. HBIG has been the standard of care for the past two decades or so. Recently, with the advent of highly active inhibitors of the ribose nucleic acid polymerase of HBV (entecavir, tenofovir), there has been growing evidence that HBIG needs to be given for shorter lengths of time; indeed, it may no longer be necessary at all. In this review, we describe genetic variants of HBV and past, present, and future prophylaxis of HBV infection during and after liver transplantation. We have reviewed the extant medical literature on the subject of infection with the HBV, placing particular emphasis upon the prevention and treatment of recurrent HBV during and after liver transplantation. For the review, we searched PubMed for all papers on the subject of “hepatitis B virus AND liver transplantation”. We describe some of the more clinically relevant and important genetic variations in the HBV. We also describe current practices at our medical centers, provide a summary and analysis of comparative costs for alternative strategies for prevention of recurrent HBV, and pose important still unanswered questions that are in need of answers during the next decade or two. We conclude that it is now rational and cost-effective to decrease and, perhaps, cease altogether, the routine use of HBIG during and following liver transplantation for HBV infection. Here we propose an individualized prophylaxis regimen, based on an integrated approach and risk-assessment.