乙肝肝硬化并发皮下脂膜炎样T细胞淋巴瘤伴噬血细胞综合征的治疗分析

目的 探讨乙肝肝硬化并发皮下脂膜炎样T细胞淋巴瘤(SPTCL)伴噬血细胞综合征(HPS)的临床特征和治疗方法。 方法 回顾性分析2014年8月第二军医大学附属东方肝胆外科医院1例乙肝肝硬化并发SPTCL伴HPS病例的临床资料。 结果 T细胞受体(TCR)表型不同则该病的侵袭性、治疗反应性及预后明显不同,伴HPS者治疗效果不佳,生存期短。 结论 乙肝肝硬化并发SPTCL伴HPS罕见,早期骨髓形态学、病理学、免疫组化及基因重排检测对确诊有重要意义,及早有效控制乙肝病毒尤为重要。早期诊断及治疗对延长患者生存期有重要意义。     

Low efficacy of entecavir therapy in adefovir‐refractory hepatitis B patients with prior lamivudine resistance

Summary. We determined the virologic response, incidence of entecavir resistance, and evolution of lamivudine and adefovir‐resistant mutants during entecavir (ETV) therapy in adefovir‐refractory patients with prior lamivudine resistance. Forty adefovir‐refractory chronic hepatitis B patients with prior lamivudine resistance who had received entecavir for ≥6 months were included and monitored for virologic response and entecavir resistance. Ten per cent of patients achieved HBV DNA < 50 copies/mL by PCR after 24 weeks of ETV therapy, and an initial virologic response was observed in 12 of 40 patients (30%). Higher pretreatment ALT (P = 0.039) and the presence of the rtL180M mutation (P = 0.038) were associated with an initial virologic response. During a mean follow‐up of 11.4 months, four patients (10%) experienced virologic breakthrough, while ETV‐resistant mutants were detected in six patients (15%). YMDD and adefovir‐resistant mutants were detected in 57 and 35% of patients at baseline, respectively. At 48 weeks of therapy, 96 and 4% of patients had YMDD and adefovir‐resistant mutants, respectively. These data suggest an early development of ETV resistance and low antiviral response during ETV therapy in adefovir‐refractory patients with prior lamivudine resistance.     

Antiviral efficacy of combination therapy with entecavir and adefovir for entecavir/lamivudine-resistant hepatitis B virus with or without adefovir resistance

There is little clinical information on the management of hepatitis B virus (HBV) that is resistant to multiple drugs including entecavir (ETV). The present retrospective cohort study assessed the antiviral efficacy of ETV/adefovir dipivoxil (ADV) combination therapy for ETV-resistant HBV with prior lamivudine (LAM) resistance, and either with or without previous ADV resistance. The cumulative probability of achieving a virological response (undetectable serum HBV DNA) was compared by Kaplan-Meier analysis and the Breslow method. Seventeen patients with ETV-resistant HBV who were treated with ETV/ADV combination therapy for at least 6 months at a tertiary care center, were included; seven had dual resistance to ETV and LAM [ADV-r(-) group] and 10 had triple resistance to ETV, LAM, and ADV [ADV-r(+) group]. The median follow-up period was 9 months (range, 6-23). A virological response was noted in seven patients after a median of 3 months (range, 3-12) of treatment; five in the ADV-r(-) group and two in the ADV-r(+) group. The cumulative probability of a virological response was significantly higher in the ADV-r(-) group than in the ADV-r(+) group (6 months cumulative probability, 57.1% vs. 11.1%). In conclusion, ETV/ADV combination therapy led to virological responses in five of seven patients with resistance to ETV and LAM, but a significantly poorer response in patients with prior ADV resistance than in those without prior ADV resistance. Therefore, ETV/ADV combination therapy could be a useful therapeutic option for ETV- and LAM-resistant HBV without prior ADV resistance.     

Phenotypic assay of a hepatitis B virus strain carrying an rtS246T variant using a new strategy

Phenotypic assays of hepatitis B virus (HBV) play an important role in research related to the problem of drug resistance that emerges during long-term nucleot(s)ide therapy in patients with chronic hepatitis B. Most of the phenotypic assay systems that are available currently rely on the transfection of recombinant replication-competent HBV DNA into hepatoma cell lines. Cloning clinical HBV isolates using conventional digestion-and-ligation techniques to generate replication-competent recombinants can be very difficult because of the sequence heterogeneity and unique structure of the HBV genome. In this study, a new strategy for constructing an HBV 1.1× recombinant was developed. The core of this strategy is the "fragment substitution reaction" (FSR). FSR allows PCR fragments to be cloned without digestion or ligation, providing a new tool for cloning fragments or genomes amplified from serum HBV DNA, and therefore making the assay of HBV phenotypes more convenient. Using this strategy, a phenotypic assay was performed on an HBV strain carrying an rtS246T variant isolated from a patient with chronic hepatitis B that was only responsive partially to entecavir therapy. The results indicated that this strain is sensitive to entecavir in vitro.     

恩替卡韦治疗乙型肝炎肝硬化短期疗效分析

目的探讨恩替卡韦治疗乙肝肝硬化的短期临床疗效。方法回顾性分析我院自2009年9月～2011年2月收治的126例乙肝肝硬化患者,随机分为观察组67例给予恩替卡韦治疗,对照组59例采用拉米夫定治疗,比较治疗后6周、12周、24周两组患者乙肝病毒DNA(HBV-DNA)阴转率、治疗24周后HBV-DNA水平、总胆红素(TBil)、天冬氨酸转氨酶(AST)、丙氨酸转氨酶(ALT)、Cllild-Pugh评分、疾病进展情况等指标。结果①HBV-DNA阴转率:治疗6周、12周、24周后,观察组优于对照组,P<0.05。②TBil、HBV-DNA水平:治疗24周后,观察组优于对照组,P<0.05。③Child-Pugh评分:两组治疗前后比较,Child-Pugh评分均有显著改善,P<0.05;观察组改善优于对照组,P<0.05。结论恩替卡韦短期应用治疗乙型肝炎肝硬化效果确切。     

Can we stop nucleoside analogues before HBsAg loss?

Most of the current guidelines and the existing data suggest that long‐term therapy with nucleos(t)ide analogue(s) [NA(s)] may be stopped in carefully selected chronic hepatitis B patients who remain HBsAg positive. In particular, NA(s) may be discontinued in such patients without pre‐existing cirrhosis who achieved long‐term on‐therapy virological remission (>12 months of HBeAg seroconversion and HBV DNA undetectability for initially HBeAg‐positive cases; ≥3 years of HBV DNA undetectability for HBeAg‐negative cases) and are expected to remain under close follow‐up after NA(s) discontinuation. The majority of patients will develop post‐NA(s) virological relapses and a proportion of them will have biochemical relapses and occasionally flares, but prompt retreatment can reintroduce remission. No reliable predictor(s) of post‐NA(s) relapses have been identified so far. HBsAg loss develops in a progressively increasing proportion of chronic hepatitis B patients who discontinue NA(s) with HBsAg loss rates being higher in Caucasian patients with HBeAg‐negative chronic hepatitis B. Follow‐up at least every 3 months for the first year seems to be appropriate for all chronic hepatitis B patients who discontinue NA(s), while HBeAg‐negative patients need to be followed more closely (monthly) during the first 3 months. Predefined criteria for retreatment are quite important, and the best candidates for retreatment are probably the patients with persistent (≥3 months) liver disease activity and those with severe flares.     

Baseline and kinetics of serum hepatitis B virus RNA predict response to pegylated interferon‐based therapy in patients with hepatitis B e antigen‐negative chronic hepatitis B

Serum hepatitis B virus (HBV) RNA has emerged as a novel biomarker of treatment response. This study aimed to investigate the role of this marker in predicting long‐term outcome of patients with hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B (CHB) receiving pegylated interferon (PEG‐IFN)‐based therapy. Serial serum samples from 91 patients with HBeAg‐negative CHB previously treated with PEG‐IFN alone or combined with entecavir in a randomized trial were retrospectively analysed. HBV RNA quantification was examined by droplet digital PCR. At the end of 3 years post‐treatment follow‐up, maintained virological response (MVR, HBV DNA < 2000 IU/mL), and hepatitis B surface antigen (HBsAg) clearance were achieved in 37.4% (34/91) and 7.7% (7/91), respectively. Baseline serum HBV RNA concentrations correlated with HBV DNA and covalently closed circular DNA but did not correlate with HBsAg levels. Multiple regression analysis showed that pre‐treatment HBV RNA and HBsAg were independently associated with MVR and HBsAg clearance. Baseline HBV RNA (cut‐off 2.0 log₁₀ copies/mL) had a positive predictive value (PPV) and a negative predictive value in predicting MVR of 80.8% and 80.0%, respectively. At the same cut‐off value, PPV and NPV for predicting HBsAg clearance were 30.8% and 95.4%, respectively. At week 12 during therapy, HBV RNA level ≥ 2 log₁₀ copies/mL displayed high NPVs of achieving MVR and HBsAg clearance (95% and 100%, respectively). In conclusion, the measurement of HBV RNA prior to PEG‐IFN‐based therapy could identify patients with high probability of MVR. In addition, HBV RNA kinetics may serve as a promising “stopping rule” in patients infected with HBV genotypes B or C.     

Current management of hepatitis B virus infection before and after liver transplantation

The progress in treatment against hepatitis B virus (HBV) has substantially improved the outcome of all HBV‐infected patients. We systematically reviewed the existing data in the management of HBV transplant patients in order to assess the optimal regimen in the pretransplant setting, for post‐transplant prophylaxis and for therapy of HBV recurrent infection. All data suggest that an effective pretransplant anti‐HBV therapy prevents post‐transplant HBV recurrence. Pretransplant therapy has been based on lamivudine with addition of adefovir upon lamivudine resistance, but the use of newer, potent high‐genetic barrier agents is expected to improve long‐term efficacy. Moreover, it may lead to improvement of liver function, which sometimes removes the need for transplantation, although more objective criteria for removal from waiting lists are required. After liver transplantation, the combination of HBV immunoglobulin and one nucleos(t)ide analogue, mostly lamivudine, is currently the best approach, almost eliminating the probability of HBV recurrence. Treatment of post‐transplant HBV recurrence has been mainly studied with lamivudine, but it will be most effective with entecavir and tenofovir, which have a low risk of resistance. In conclusion, the newer anti‐HBV agents improve the treatment of HBV both pretransplant and post‐transplant. HBV immunoglobulin is still used in combination with an anti‐HBV agent for post‐transplant prophylaxis. Monoprophylaxis with one of the new anti‐HBV agents might be possible, particularly in patients preselected as having a low risk of HBV recurrence, but further data are needed and strategies to ensure compliance must be used.     

An alternative and robust synthesis of [13C4]Baraclude® (entecavir)

Stable isotope‐labeled [¹³C₄]entecavir (1) was prepared in 11 steps. Commercially available [¹³C]guanidine hydrochloride and diethyl[1,2,3‐¹³C₃]malonate were condensed to yield 2‐amino[2,4,5,6‐¹³C₄]pyrimidine‐4,6‐diol (8). This was converted to the desired purine (7) in five steps. Introduction of the chiral epoxide was followed by subsequent deprotection to give [¹³C₄]entecavir (1), in an overall yield of 5.7% from labeled precursors. The chemical purity of the title compound was determined to be >99% by HPLC. The isotopic distribution was determined by mass spectrometry to be 282[M + 4], 98.4%; 281[M + 3], 1.6%; and 278[M + 0], <0.1%. Copyright © 2013 John Wiley & Sons, Ltd.