Antiviral therapy for hepatitis B virus‐related decompensated cirrhosis

Antiviral therapy is important in patients with hepatitis B virus (HBV)‐related decompensated cirrhosis. This therapy is beneficial in most patients for the stabilization or improvement of liver disease; however, advanced cirrhosis with a high Child–Pugh or model for end‐stage liver disease (MELD) score may have progressed and does not benefit from antiviral therapy. It is important to identify patients with severe decompensated cirrhosis who will not improve under antiviral therapy and who require liver transplantation as early as possible. Entecavir (ETV) or tenofovir disoproxil fumarate (TDF) is the first‐line therapy for nucleos(t)ide analogue (NA)‐naive patients with decompensated cirrhosis due to their potent and prompt HBV suppressive effect and low rate of drug‐resistant mutations. Patients on antiviral therapy should be monitored for virological and clinical response, compliance, drug resistance and adverse effects as well as surveillance for hepatocellular carcinoma (HCC). Additional studies of TDF and ETV are necessary to determine the optimal agent(s) for treating naive patients and those with drug‐resistant decompensated cirrhosis. In order to evaluate the effectiveness of NA for the treatment of decompensated cirrhotic patients in the real world, high quality observational studies such as registration studies of antiviral therapy for HBV‐related cirrhosis and a long‐term follow‐up in China, where a large number of such patients are found, are recommended.     

Prognosis of 1169 hepatitis C chronically infected patients with decompensated cirrhosis in the predirect‐acting antiviral era

At a population level, little is known regarding the risk of liver‐ and nonliver‐related mortality and hospitalization and the development of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)‐infected patients with decompensated cirrhosis (DC). This large‐scale national record‐linkage study estimates these outcomes following first hospital admission for DC. Record‐linkages between national HCV diagnosis and clinical databases and the national inpatient hospital episode database and mortality register were conducted to follow‐up the disease course of all identified HCV‐diagnosed and chronically infected persons. The study population consisted of 1169 HCV chronically infected persons who had a first hospital admission for DC within the period 1994‐2013. We observed an overall average annual percentage change of 12.6% in new DC patients (from 63 in 1994‐1999 to 541 in 2009‐2013), with no evidence for any improvement in the relative risks of liver‐related or all‐cause death over time. Between 1 January 1994 and 31 May 2014, 722 and 95 DC patients had died of a liver‐ and a nonliver‐related cause, respectively, and 106 patients had a subsequent first admission for HCC. The 5‐year cumulative incidence of liver‐related mortality, nonliver‐related mortality and first subsequent HCC admission was 61.3%, 8.2% and 8.8%, respectively. The health burden in HCV‐infected patients associated with development of decompensated cirrhosis has increased dramatically over the last 20 years. Our findings establish the baseline mortality and HCC progression rates in DC patients against which the impact of new antiviral therapies can be measured.     

失代偿期丙型肝炎肝硬化患者长期随访研究

目的通过对失代偿期丙型肝炎肝硬化患者的长期随访,总结分析失代偿期丙型肝炎肝硬化的疾病进展及预后。方法随访2008年1月—2010年2月我院收治的195例失代偿期丙型肝炎肝硬化住院患者,总结其临床资料,进行生存分析。结果失代偿期丙型肝炎肝硬化首发临床表现有腹水(65.1%)、食管胃底静脉曲张破裂出血(17.4%)、自发性细菌性腹膜炎(16.4%)及肝性脑病(1.0%)。主要死因为原发性肝癌(27.6%)、食管胃底静脉曲张破裂出血及失血性休克(24.1%)、肝性脑病及脑水肿(15.5%)、肝肾综合征(8.6%)、多脏器衰竭(8.6%)和感染性休克(3.4%),12.1%的患者死因不详。失代偿期丙型肝炎肝硬化患者1、3、5年生存率分别为97.4%、85.3%、65.7%。1、3、5年原发性肝癌发病率分别为1.0%、6.4%、16.4%。Child-Turcotte-Pugh(CTP)分级C级患者与A级和B级相比,生存时间短,病死率高,差异有统计学意义。结论失代偿期丙型肝炎肝硬化病情进展较快,合并症较多,病死率高,预后差,CTP分级与生存时间密切相关。     

Inhibitory effect of branched-chain amino acid granules on progression of compensated liver cirrhosis due to hepatitis C virus

Background. A phase II randomized controlled trial was conducted in patients with compensated liver cirrhosis to investigate the inhibitory effect of branchedchain amino acid (BCAA) granules for oral use (TK-98) on disease progression. Methods. Patients who had compensated liver cirrhosis due to hepatitis C virus with baseline serum albumin levels between 3.6 and 4.5 g/dl were assigned to the TK-98 group, which was treated with BCAA granules (TK-98) for 168 weeks, or to a control group (no treatment). Results. No symptoms indicating decompensated cirrhosis, including ascites, edema, and hepatic encephalopathy were reported in either the TK-98 or control group during the study observation period. Hepatocellular carcinoma (HCC) was noted in eight of the 39 patients studied, and of these three received TK-98 (15.8%) and five were untreated (25.0%). A time-to-event analysis for the effect of BCAA therapy on development of HCC revealed no statistically significant differences between the two groups. However, an additional analysis of data from a subgroup with a baseline serum albumin level of <4.0 g/dl showed that the incidence of HCC was likely to be lower in BCAA-treated patients. Conclusions. BCAA may inhibit hepatic carcinogenesis in patients with compensated cirrhosis with a serum albumin level of <4.0 g/dl.     

慢性HCV感染DAA应答特点和长期预后观察研究

目的 本研究旨在观察不同疾病进展阶段的HCV感染者直接抗病毒药物(direct-acting antiviral agents,DAA)治疗的应答特点和长期预后.方法 纳入2016年7月—2017年3月就诊于我中心的慢性HCV感染者127例,其中慢性丙型肝炎(chronic hepatitis C,CHC)患者85例,代偿期肝硬化(compensated-liver cirrhosis,CLC)患者32例,失代偿期肝硬化(decompensated-liver cirrhosis,DLC)患者10例.DAA治疗12或24周.比较3组患者HCV RNA转阴时间、停药后12周持续病毒学应答(sustained virologic response 12,SVR12)率以及停药后2年的转归情况.结果 所有CHC、CLC、DLC患者均完成DAA治疗.CHC、CLC和DLC患者的SVR12率分别为98.82％(84/85)、96.88％(31/32)和100％(10/10);CHC患者HCV RNA转阴时间明显早于CLC和DLC患者(P均<0.05).在2年随访期间,1例CLC患者发生病毒学复发,2例DLC患者分别出现肝功能恶化和肝细胞癌.结论 目前常用的DAA治疗方案对CHC、CLC和DLC的患者均有高效的抑制病毒复制的作用,并且SVR12率在96％～100％之间,有很高治愈率.对于肝硬化患者停药后仍须监测肝癌的发生或个别病例HCV复发等情况.     

Liver iron is predictive of death in alcoholic cirrhosis: a multivariate study of 229 consecutive patients with alcoholic and/or hepatitis C virus cirrhosis: a prospective follow up study

BACKGROUND/AIMS: A study was undertaken of liver biopsy samples from 229 consecutive patients with alcoholic or hepatitis C virus related cirrhosis who were prospectively followed until January 1996 to evaluate the influence of liver iron content on survival and the occurrence of hepatocellular carcinoma. METHODS: Hepatic iron content was measured with a validated semiquantitative score, and its predictive value for survival and the occurrence of hepatocellular carcinoma was assessed. RESULTS: 130 patients had detectable iron at enrollment. During follow up (57 (28) months), 95 patients died and 39 patients developed hepatocellular carcinoma. No significant relation was found between hepatic iron and the occurrence of hepatocellular carcinoma. Conversely, the presence of iron was predictive of death in alcoholic patients (p = 0.007) by the log rank test but not in patients with hepatitis C virus related (p = 0.71) or mixed (p = 0.98) cirrhosis. The predictive value of hepatic iron content in patients with alcoholic cirrhosis was confirmed by the Cox model using either a binary coding (p = 0.009; relative risk = 2.27; 95% confidence interval 1.2 to 4.19) or the continuous values (p = 0.002). CONCLUSIONS: These results suggest that hepatic iron enhances liver lesions caused by alcohol but not those caused by hepatitis C virus.     

Hepatitis C virus genotypes: distribution and clinical significance in patients with cirrhosis type C seen at tertiary referral centres in Europe

The aim of this study was to evaluate the distribution and clinical significance of hepatitis C virus (HCV) genotypes in European patients with compensated cirrhosis due to hepatitis C (Child class A) seen at tertiary referral centres. HCV genotypes were determined by genotype-specific primer PCR in 255 stored serum samples obtained from cirrhotics followed for a median period of 7 years. Inclusion criteria were biopsy-proven cirrhosis, absence of complications of cirrhosis and exclusion of all other potential causes of chronic liver disease. The proportion of patients with types 1b, 2, 3a, 1a, 4 and 5 were 69%, 19%, 6%, 5%, 0.5% and 0.5%, respectively. Kaplan–Meier 5-year risk of hepatocellular carcinoma (HCC) was 6% and 4% for patients infected by type 1b and non-1b, respectively ( P =0.8); the corresponding figures for decompensation were 18% and 7% ( P =0.0009) and for event-free survival were 79% and 89% ( P =0.09), respectively. After adjustment for baseline clinical and serological features, HCV type 1b did not increase the risk for HCC [adjusted relative risk=1.0 (95% confidence interval=0.47–2.34)], whereas it increased the risk for decompensation by a factor of 3 (1.2–7.4) and decreased event-free survival by a factor of 1.7 (0.9–3.10). In conclusion, type 1b and, to a lesser extent, type 2, are the most common HCV genotypes in European patients with cirrhosis. HCV type 1b is not associated with a greater risk for HCC, but increases the risk for decompensation by threefold in patients with cirrhosis.     

抗病毒治疗对失代偿期乙型肝炎肝硬化患者远期预后的影响

目的探讨抗病毒治疗对失代偿期乙型肝炎肝硬化患者远期预后的影响。方法收集2009年5月-2012年5月于资阳市乐至县人民医院住院次数≥3次的失代偿期乙型肝炎肝硬化患者132例。根据治疗方法不同分为对照组(n=51)和观察组(n=81),门诊和电话随访5年,均行Child-Pugh评分和MELD评分,观察HBV DNA下降、阴转情况及肝功能指标,随访结束时对比两组临床结局。计量资料组间比较采用t检验,计数资料组间比较采用χ2检验。结果观察组肝癌、肝移植发生率及病死率均显著低于对照组(χ2值分别为4.32、4.33、4.71,P值均0.001);观察组治疗后HBV DNA载量显著低于同组治疗前(t=20.60,P0.001);观察组治疗后HBV DNA载量显著低于对照组治疗后(t=16.40,P0.05);观察组治疗后HBV DNA累积转阴率显著高于对照组(88.89%vs 6.67%,P0.05);观察组治疗后血清白蛋白水平显著高于对照组,TBil、ALT水平显著低于对照组(t值分别为6.77、16.60、11.67,P值均0.001);与治疗前比较,两组治疗后TBil、ALT水平显著下降(观察组:t值分别为25.18、23.33,P值均0.001;对照组:t值分别为6.15、7.20,P值均0.001);观察组治疗后白蛋白水平显著上升(t=10.08,P0.001);观察组治疗后Child-Pugh评分和MELD评分均显著低于对照组(t值分别为2.27、2.24,P值均0.05);与治疗前比较,两组治疗后Child-Pugh评分和MELD评分均显著下降(观察组:t值分别为9.18、8.17,P值分别为0.001、0.03;对照组:t值分别为2.93、3.12,P值分别为0.01、0.04)。结论长期抗病毒治疗能够改善失代偿期乙型肝炎肝硬化患者远期预后,提高5年存活率。     

Sustained virologic response after eight weeks of treatment with sofosbuvir,ledipasvir, and ribavirin in a decompensated cirrhotic patient with hepatitis C virus genotype 1b

A 68‐year‐old Japanese man with decompensated cirrhosis due to hepatitis C virus (HCV) genotype 1b infection was treated with sofosbuvir (SOF; 400 mg/day), ledipasvir (LDV; 90 mg/day), and ribavirin (RBV; 400 mg/day). Before treatment, his Child–Pugh and Model for End‐Stage Liver Disease (MELD) scores were 10 (class C) and 13 points, respectively. Although RBV was initially given at two‐thirds the normal dose due to anemia, his hemoglobin level gradually declined, and RBV was reduced to 200 mg daily on day 11, and 200 mg every other day on day 14. His alanine aminotransferase level gradually decreased during combination therapy; and HCV‐RNA was undetectable on day 28. He complained of fatigue from day 49, and RBV was ceased. On day 56, he asked to discontinue treatment because of strong fatigue and insomnia. As hepatic encephalopathy occurred just after the cessation of direct‐acting antivirals, diuretics were discontinued, and treatment with synthetic disaccharides and intractable antibiotics were given, after which his consciousness returned to normal. Ascites gradually disappeared, and a sustained virologic response (SVR) was achieved. At 1.5 years after treatment, his Child–Pugh and MELD scores had improved to 6 (class A) and 10 points, respectively. Although he did not experience hepatic encephalopathy during the observation period, his blood ammonia concentration persistently increased. We reported a case of decompensated cirrhosis in a patient who achieved SVR with SOF/LDV plus RBV for 8 weeks. Although his liver function improved after treatment, careful long‐term observation is required for complications of liver cirrhosis, even after HCV elimination.     

抗病毒治疗对失代偿期乙型肝炎肝硬化患者经颈静脉肝内门体分流术预后的影响

目的探讨抗病毒治疗对失代偿期乙型肝炎肝硬化患者经颈静脉肝内门体静脉分流术(TIPS)预后的影响。方法回顾性分析2008年1月-2011年12月行TIPS预防静脉曲张破裂再出血的失代偿期乙型肝炎肝硬化患者110例,按其是否使用抗病毒药物,分为TIPS联合抗病毒组(58例)与TIPS组(52例),计量资料组间比较采用t检验或Wilcoxon秩和检验,计数资料组间比较采用χ2检验,累积生存率、再出血率、支架通畅率和肝细胞癌发生率采用Kaplan-Meier生存分析及log-rank检验。结果 TIPS联合抗病毒组和TIPS组患者TIPS术后1、3和5年累积生存率分别为93.1%、86.1%、77.7%和88.5%、64.9%、59.7%,TIPS联合抗病毒组的累积生存率显著优于TIPS组(χ2=6.833,P=0.009)。TIPS联合抗病毒组的病毒学应答率随着抗病毒治疗时间的延长而逐渐升高。两组累积静脉曲张再出血率、支架通畅率、肝细胞癌发生率的差异均无统计学意义(P值均0.05)。结论抗病毒治疗可改善失代偿期乙型肝炎肝硬化TIPS术后患者的生存率。     

拉米夫定在失代偿期肝硬化的临床应用研究

为观察拉米夫定对慢性乙型肝炎所致失代偿期肝硬化的疗效对9例失代偿肝硬化患者应用拉米夫定的治疗结果进行总结。9例患者，HBsAg、HBV－DNA均阳性，其中6例Child-Pugh分级为B级，3例为C级。口服用拉米夫定每日100mg，疗程半年。8例患者拉米夫定治疗后血清HBV－DNA均转为阴性，肝功能保持持续稳定，Child-Pugh分级下降≥2。1例患者死亡。拉米夫定通过有效抑制HBV－DNA复制，而改善失代偿肝硬化的肝功能。     

Determinants of early mortality and benefits of lamivudine therapy in patients with hepatitis B virus-related decompensated liver cirrhosis

Chronic hepatitis B infection (HBV) is a major health problem worldwide. The prognosis is grave for patients with HBV-related decompensated liver cirrhosis (LC). We evaluated the effectiveness and the determinants of early mortality of lamivudine treatment in patients with HBV-related decompensated LC. Thirty patients with HBV-related decompensated LC and active viral replication were treated with lamivudine 100 mg daily for a median duration of 9 months. Among these patients, five patients died within 3 months. Two patients were lost to follow-up at week 8 and 9. One patient was treated for <6 months. Twenty-two patients were treated over 6 months. Univariate analysis revealed that the total bilirubin (P = 0.008), prothrombin time (P = 0.004), Child-Turcotte-Pugh score (P = 0.005), the model of efd-stage liver disease score (P = 0.004) and stage III hepatic encephalopathy (P = 0.001) were predictive factors of early mortality. Multivariate analysis revealed that the independent factor associated with early mortality was stage III encephalopathy. Among 22 patients, liver function improved markedly after lamivudine therapy. Of the nine hepatitis B e antigen (HBeAg)-positive patients, three had HBeAg seroconversion. Two patients had YMDD mutant and virological breakthrough at 41 and 46 weeks. One of the two had hepatocellular carcinoma and died of hepatic failure at week 125; the other received adefovir and is doing well. Lamivudine appeared to have benefits in viral suppression and significant improvement in liver function in patients with HBV-related decompensated LC. As noted in prior studies, poor baseline liver function is associated with a poor prognosis in Asian patients with decompensated HBV cirrhosis treated with lamivudine.     

239例肝硬化失代偿期患者的短期预后评估

目的评价终末期肝病模型（MELD）、MELD-Na、Child—Turcotte—Pugh（CTP）和包含血肌酐值的CTP（CrCTP）评分对肝硬化患者短期预后的评估意义。方法回顾性收集自2005年1月-2007年12月我院收治的239例肝硬化失代偿期患者的病例资料,分别应用CTP、CrCTP、MELD和MELD—Na模型进行评分,并了解其3个月内的病死率。以受试者工作特征曲线（ROC）下面积（AUC）衡量各评分系统预测肝硬化失代偿期患者短期预后的能力,并运用Z检验比较各系统的预测能力。结果30例患者在3个月内死亡。死亡组患者的CTP、CrCTP、MELD和MELD—Na分值（分别为11．47±2．46、12,47±2．05、19．70±6．71、27．97±10．79）与生存组（分别为8．73±2．03、8．95±2．13、10．92±4．74、14．48±6．55）相比差异有统计学意义（P〈0．001）。CTP、CrCTP、MELD和MELD-Na评分对肝硬化失代偿期患者3个月预后评估的ROC曲线下面积分别为0．799、0．822、0．873、0．870。结论CTP、CrCTP、MELD和MELD-Na模型均可有效预测我国肝硬化失代偿期患者的短期预后;MELD评分在判断肝硬化失代偿期患者的短期预后方面优于CTP;在CTP中引入血肌酐值即CrCTP评分可以提高对肝硬化失代偿患者短期预后的判断准确性;MELD-Na模型未显示比MELD更佳的预测能力。