丙型肝炎各级肝硬化患者的抗病毒治疗策略

丙型肝炎病毒（HCV）感染是引起肝硬化、终末期肝病以及肝细胞癌的重要原因。慢性丙型肝炎的标准化治疗方案———聚乙二醇化干扰素α联合利巴韦林已取得了良好的效果,但进展至肝硬化尤其是失代偿期的患者多难以耐受干扰素的不良反应,给抗病毒治疗带来困难。面对我国丙型肝炎肝硬化比例较高、肝移植实施困难、对标准的抗病毒治疗方案应答率高的特点,参考国际指南,作者在国内率先探索和提出了丙型肝炎肝硬化分级标准及相应的抗病毒治疗策略,并进行了相关的临床研究和应用。依据作者提出的丙型肝炎肝硬化的分级方法,先采取不同的处置方法缓解脾亢或减少副作用后,再采用标准化抗病毒治疗方案,可以有效地延缓肝硬化的进展,减少HCV感染相关并发症,最终提高患者生活质量。     

慢性丙型肝炎抗病毒治疗后复发的影响因素分析

目的 探讨慢性丙型肝炎(CHC)抗病毒治疗后复发的预测因素及时间规律.方法 聚乙二醇干扰素联合利巴韦林治疗CHC.荧光定量PCR法检测HCV RNA,CE1区测序法检测HCV基因型.结果 113例患者中有100例获得治疗末病毒学应答,14例复发.HCV1型复发率(21.6％)高于HCV2型(13.3％)、HCV3型(10.3％)和HCV6型(5.3％)(P=0.345).年龄≤40岁的复发率(10.8％)低于年龄＞40岁者(20.6％);男性(9.8％)低于女性(20.5％),高ALT( 8.6％)低于低ALT( 21.4％),但差异均无统计学意义(P =0.204、0.133、0.068).高HCV RNA的复发率(14.3％)与低HCV RNA(13.7％)相近(P=0.936).获得完全快速病毒学应答(RVR)的复发率(8.5％)低于仅获得部分RVR(23.1％)和未获得RVR( 33.3％);获得完全早期病毒学应答(EVR)(13.7％)低于仅获得部分EVR( 50.0％);但差异均无统计学意义(P=0.174、0.148).停药后3个月内复发多见,未见停药6个月以上复发者.结论 治疗过程中病毒转阴越早复发率越低,复发在3个月内最多.     

慢性丙型肝炎抗病毒治疗后复发的治疗

最近10年来慢性丙型肝炎治疗有较大进展，从单用α干扰素（interferon-α，IFN-α）治疗发展到以IFN与利巴韦林（RBV）联合治疗。新近几年，由于pegyloated聚乙二醇干扰素（PEG）的应用，提倡PEGIFN／RBV联合治疗，提高了SVR率。     

如何提高代偿期丙型肝炎肝硬化患者抗病毒治疗的疗效

丙型肝炎病毒感染是肝硬化和肝细胞癌(HCC)的重要病因.HCV感染后20年肝硬化的发生率约为12.5％.2005年,美国丙型肝炎肝硬化患者为21.25万例,估计到2015年这一数字会增加到37.5万例,按美国的计算标准,2005年世界范围内丙型肝炎肝硬化患者约为780万例,2015年约为1380万例[1].目前慢性丙型肝炎(chronic hepatitis C,CHC)的持续病毒应答(sustained virologic response,SVR)率在1型HCV感染患者已经超过66％[2];2、3型HCV感染患者在80％以上;但丙型肝炎肝硬化患者抗病毒治疗后的SVR率仅为30％左右[3].     

丙型肝炎抗病毒治疗研究进展

丙型肝炎由于进展隐匿、慢性率高及预后不良而倍受关注。研究发现，约20％慢性丙型肝炎患者将进展为肝硬化，约2．5％最终罹患肝癌。据估计，全球有1．7亿丙型肝炎病毒（HCV）携带者，我国人群HCV感染率约在3％左右。以干扰素为基础的治疗在临床上一直居于主导地位，特别是聚乙二醇化干扰素（Peg—IFN）联合利巴韦林的应用使病毒学应答率明显提高。但是，疗程长、有效率低、不良反应大等问题仍未得到根本解决。     

肝移植术后丙型肝炎抗病毒治疗进展

肝移植时若受体可检出丙型肝炎病毒核糖核酸(HCV RNA),移植肝会迅速感染HCV,称为HCV复发。HCV复发可导致移植肝纤维化进展、肝硬化等,显著降低移植肝存活率。有效清除HCV是改善患者预后的关键。移植术后患者只要可检出HCV RNA,均应抗病毒治疗,并应在病情稳定后尽早开始。目前与免疫抑制剂药物相互作用(DDI)较少、安全性高的泛基因型直接抗病毒药物已被推荐用于移植术后患者。临床上应根据患者的肝肾功能、DDI等选择不同方案。现对肝移植术后HCV感染的抗病毒治疗现状及进展进行综述。     

我国丙型肝炎抗病毒治疗现状与小分子药物的应用前景

仅仅在2年前(2011年3月)欧洲肝病学会发布新版《丙型肝炎指南》的时候,聚乙二醇干扰素α(Peg-IFN α)联合利巴韦林(RBV)仍然是慢性丙型肝炎的标准治疗方案.2年来,抗HCV的小分子药物出现空前快速发展的局面,其密集的程度是历史上其他疾病领域从未有过的,并取得了突破性的进展.首先是2011年5月两种直接抗HCV药物在美国和欧洲陆续被批准上市,即Telaprevir和Boceprevir两个蛋白酶抑制剂.2年来,又有近20种药物正在进行联合或不联合Peg-IFN或RBV的2期和(或)3期临床试验.     

慢性丙型肝炎治疗后复发的相关因素及处理对策

临床实践中发现,慢性丙型肝炎(chronic hepatitis C,CHC)患者在经标准化治疗获得病毒学应答后,仍有部分患者停药后出现复发,但有关的临床研究资料有限.有鉴于此,中华肝脏病杂志组织部分专家进行了研讨,依据现有的临床研究文献及循证医学临床资料,分析总结CHC复发再治疗的临床经验,提出治疗方案的建议,供国内同道参考,并在临床实践过程中依据新的临床医学证据进行修改和更新.     

慢性丙型肝炎的抗病毒治疗及早期疗效预测

目前,在全世界范围内丙型肝炎病毒(HCV)感染者已达1.7亿,其中约70%～80%的受感染者可发展成为慢性丙型肝炎(chronic hepatitis C).慢性丙型肝炎患者经过10～30年,其中20%可发展为肝硬化及出现相关并发症,这其中又有约1%～4%发展为肝细胞癌.自1989年Houghton等发现HCV以来,对HCV的认识及慢性丙型肝炎的诊断与治疗研究都有了很大的进展. 慢性丙型肝炎的抗病毒治疗经历了由单一干扰素治疗到干扰素联合利巴韦林再到目前长效干扰素以及长效干扰素联合利巴韦林治疗的发展过程.抗病毒治疗的疗效也不断提高,仅仅在10年前抗病毒治疗的持久病毒应答率仅达5%～10%.随着治疗的不断改进,目前抗病毒治疗的疗效几乎提高了近10倍.抗病毒治疗不仅可抑制HCV病毒复制,改善肝脏炎症活动,防止肝纤维化及肝硬化的进展,也可防止和减少肝细胞癌的发生.本文对慢性丙型肝炎的抗病毒治疗、HCV对治疗应答的病毒动力学以及早期疗效预测等3个方面作一综述.     

丙型肝炎后肝硬化伴白癜风的抗病毒治疗1例

一、临床资料患者女性,50岁,体质量60kg,因体检发现抗-HCV阳性、腹胀20d于2009年9月2日入院.20年前于当地献血600ml,并回输血浆.5年前患白癜风,未予药物治疗,间断行激光治疗.皮肤、巩膜无黄染,头皮可见5个类圆形直径1.0～ 2.5cm的白斑,可见肝掌,颈前可见2个蜘蛛痣,心、肺听诊未闻及异常,肝、脾肋下未触及,双下肢无水肿.     

Prevention of hepatitis C recurrence after liver transplantation: An update

Hepatitis C related liver failure and hepatocarcinoma are the most common indications for liver transplantation in Western countries.Recurrent hepatitis C infection of the allograft is universal and immediate following liver transplantation,being associated with accelerated progression to cirrhosis,graft loss and death.Graft and patient survival is reduced in liver transplant recipients with recurrent Hepatitis C virus(HCV) infection compared to HCV-negative recipients.Many variables may impact on recurrent HCV liver disease.Overall,excess immunosuppression is believed to be a key factor;however,no immunosuppressive regimen has been identified to be more beneficial or less harmful.Donor age limitations,exclusion of moderately to severely steatotic livers and minimization of ischemic times could be a potential strategy to minimize the severity of HCV disease in transplanted subjects.After transplantation,antiviral therapy based on pegylated IFN alpha with or without ribavirin is associated with far less results than that reported for immunocompetent HCV-infected patients.New findings in the field of immunotherapy and genomic medicine applied to this context are promising.     

Natural history,treatment and prevention of hepatitis C recurrence after liver transplantation: Past,present and future

Hepatitis C virus (HCV)-related liver disease, including cirrhosis and hepatocellular carcinoma is the main indication for liver transplantation (LT) worldwide. Post-transplant HCV re-infection is almost universal and results in accelerated progression from acute hepatitis to chronic hepatitis, and liver cirrhosis. Comprehension and treatment of recurrent HCV infection after LT have been major issues for all transplant hepatologists and transplant surgeons for the last decades. The aim of this paper is to review the evolution of our knowledge on the natural history of HCV recurrence after LT, including risk factors for disease progression, and antiviral therapy. We will focus our attention on possible ways (present and future) to improve the final long-term results of LT for HCV-related liver disease.     

Pharmaceutical management of hepatitis B and C in liver and kidney transplant recipients

The combination of hepatitis B immune globulin with entecavir or tenofovir (at least for a certain period of time) seems to be the most reasonable prophylaxis against recurrent hepatitis B after liver transplantation. Entecavir represents an attractive option for treatment of naïve kidney transplant recipients, because of its high efficacy and the low rates of resistance. However antiviral treatment should be individualized in the view of kidney function and the previous resistance. To date, new captivating therapeutic strategies could make interferon-free regimens viable for treatment of hepatitis C virus positive liver transplant recipients. The recent combinations of sofosbuvir with simeprevir or daclatasvir or ledipasvir plus/minus ribavirin have boosted the on treatment and sustained virological response to rates approaching 100% within liver transplant recipients with recurrent chronic hepatitis C (CHC). Preliminary data showed that the second generation direct oral antivirals could result to high treatment rates of recurrent CHC in kidney transplant recipients as well. Ongoing studies will clarify the optimal treatment of recurrent CHC in kidney transplant recipients.     

Post-liver transplant hepatitis C virus recurrence: An unresolved thorny problem

Hepatitis C virus (HCV)-related cirrhosis represents the leading cause of liver transplantation in developed, Western and Eastern countries. Unfortunately, liver transplantation does not cure recipient HCV infection: reinfection universally occurs and disease progression is faster after liver transplant. In this review we focus on what happens throughout the peri-transplant phase and in the first 6-12 mo after transplantation: during this crucial period a completely new balance between HCV, liver graft, the recipient’s immune response and anti-rejection therapy is achieved that will deeply affect subsequent outcomes. Nearly all patients show an early graft reinfection, with HCV viremia reaching and exceeding pre-transplant levels; in this setting, histological assessment is essential to differentiate recurrent hepatitis C from acute or chronic rejection; however, differentiating the two patterns remains difficult. The host immune response (mainly cellular mediated) appears to be crucial both in the control of HCV infection and in the genesis of rejection, and it is also strongly influenced by immunosuppressive treatment. At present no clear immunosuppressive strategy could be strongly recommended in HCV-positive recipients to prevent HCV recurrence, even immunotherapy appears to be ineffective. Nonetheless it seems reasonable that episodes of rejection and over-immunosuppression are more likely to enhance the risk of HCV recurrence through immunological mechanisms. Both complete prevention of rejection and optimization of immunosuppression should represent the main goals towards reducing the rate of graft HCV reinfection. In conclusion, post-transplant HCV recurrence remains an unresolved, thorny problem because many factors remain obscure and need to be better determined.     

Management of recurrent hepatitis C virus after liver transplantation

Chronic hepatitis C virus(HCV) infection is the leading cause of death from liver disease and the leading indication for liver transplantation(LT) in the United States and western Europe. LT represents the best therapeutic alternative for patients with advanced chronic liver disease caused by HCV or those who develop hepatocarcinoma. Reinfection by HCV of the graft is universal and occurs in 95% of transplant patients. This reinfection can compromise graft function and patient survival. In a few cases, the histological recurrence is minimal and non-progressive; however, in most patients it follows a more rapid course than in immunocompetent persons, and frequently evolves into cirrhosis with graft loss. In fact, the five-year and ten-year survival of patients transplanted because of HCV are 75% and 68%, respectively, compared with 85% and 78% in patients transplanted for other reasons. There is also a pattern of recurrence that is very severe, but rare(< 10%), called fibrosing cholestatic hepatitis, which often involves rapid graft loss. Patients who present a negative HCV viremia after antiviral treatment have better survival. Many studies published over recent years have shown that antiviral treatment of post-transplant HCV hepatitis carried out during the late phase is the best option for improving the prognosis of these patients. Until 2011, PEGylated interferon plus ribavirin was the standard of care, resulting in a sustained virological response in around 30% of recipients. The addition of protease inhibitors, such as boceprevir or telaprevir, to the standard of care, or the use of other direct-acting antiviral drugs may involve therapeutic changes in the context of HCV recurrence. This may result a better prognosis for these patients, particularly those with severe recurrence or factors predicting rapid progression of fibrosis. However, the use of these agents in LT still requires clarification in terms of safety and efficacy.     

索磷布韦/达拉他韦治疗慢性丙型肝炎患者疗效及安全性分析：一项真实世界研究

目的 观察应用索磷布韦/达拉他韦联合或不联合利巴韦林治疗慢性丙型肝炎（CHC）和丙型肝炎肝硬化（LC）患者的疗效和安全性。方法 2016年5月~2017年5月收治的丙型肝炎LC患者129例和CHC患者311例,分别给予索磷布韦/达拉他韦联合利巴韦林或索磷布韦/达拉他韦治疗12周,停药后随访12周。观察停药后12周持续性病毒学应答（SVR12）、生化学应答、肝硬度测量（LSM）和治疗期间不良反应发生情况。结果 治疗2周时,LC组血清TBIL、ALT 和AST 水平分别为（18.10±3.46） μmol/L、（32.48±9.97） IU/L和（31.99±6.65） IU/L,显著低于基线时水平【分别为（20.98±28.64） μmol/L、（97.76±106.43） IU/L和（72.47±80.81） IU/L,P<0.05】,CHC组分别为（20.15±3.48） μmol/L、（35.18±18.47） IU/L和（35.05±13.22） IU/L,显著低于基线时水平【分别为（24.07±18.12） μmol/L、（91.42±54.56） IU/L和（81.06±40.45） IU/L,P<0.05】;CHC组血清HCV RNA为（1.83±2.88） lg IU/ml,LC组为（1.67±2.34） lg IU/ml,显著低于基线时水平【分别为（6.12±1.19） lg IU/ml和（5.91±1.17）lg IU/ml,P<0.01】;CHC组LSM为（8.09±0.90）kPa,LC组为（13.32±1.47） kPa,显著低于基线时水平【分别为（11.81±3.33） kPa和（17.56±9.86） kPa,P<0.01】;两组不同基因型感染者SVR均在94%以上;多因素回归分析显示基线肝硬化或复治是不能获得SVR12的高危因素;主要不良反应为乏力和头痛。讨论 应用索磷布韦/达拉他韦联合利巴韦林治疗丙型肝炎病毒感染患者可获得极高的SVR12和生化学应答率,显著改善肝纤维化程度,且具有良好的安全性。     

丙型肝炎相关性IgA肾病1例

丙型肝炎相关性肾小球肾炎较为罕见,其临床表现与病理类型有关.肾脏病理损害以膜增殖性肾炎最常见,其次为膜性肾炎,罕见IgA肾病[1].本研究报道1例HCV感染相关性IgA肾病.     

病毒性肝炎复发患者再次肝移植的预后

目的 分析病毒性肝炎复发导致移植肝肝功能衰竭患者再次肝移植的预后情况.方法 回顾性分析2003年1月20日至2012年11月20日215例再次肝移植患者的临床资料,比较18例因肝炎复发(其中丙型肝炎8例,乙型肝炎10例)再次肝移植患者与115例因胆道并发症再次肝移植患者的移植肝的生存情况,比较丙型肝炎与乙型肝炎复发患者首次肝移植后的移植肝失功情况和再次肝移植的生存情况.预后分析采用Kaplan-Meier方法绘制生存曲线进行比较.结果 215例再次肝移植患者的病因中,胆道并发症最多,为115例(53.5％),肝炎复发18例(8.4％).肝炎复发与胆道并发症患者第2个移植肝的生存率比较差异无统计学意义(P=0.543).部分丙型肝炎复发导致的移植肝失功在首次肝移植后早期(3个月内)即出现,乙型肝炎复发患者的移植肝失功几乎全出现在首次肝移植2年后.8例丙型肝炎复发患者中,5例第2个移植肝存活＞1年,10例乙型肝炎复发患者的第2个移植肝均存活＞1年,两者比较差异无统计学意义(P=0.060).结论 肝炎复发患者与胆道并发症患者的再次肝移植预后相似.乙型肝炎复发再次肝移植患者预后良好.     

The impact of sirolimus on hepatitis C recurrence after liver transplantation

BACKGROUND

While some immunosuppression strategies may accelerate hepatitis C virus (HCV) recurrence after liver transplantation (LT), the impact of sirolimus (SRL) is not known.

OBJECTIVE

To assess the risk of biopsy-proven HCV recurrence and patient survival using known and suspected risk factors for HCV recurrence as covariates.

METHODS

A retrospective analysis of 141 consecutive patients, including 88 who received de novo SRL therapy, who had undergone a first LT for HCV cirrhosis was conducted. Known and suspected risk factor covariates including transplant era, donor and recipient age, Model for End-stage Liver Disease score, cold ischemia time, immunosuppressive drugs and steroid treatment rejection rates were used in the assessment.

RESULTS

Overall, 72.3% of the cohort developed biopsy-proven HCV recurrence. The incidence of HCV recurrence was not significantly different for patients treated with SRL (75% versus 69.8%; P=0.5). There was no difference found for time to recurrence, nor did mean activity or fibrosis scores differ at the time of initial recurrence. However, on follow-up using serial biopsies in patients with recurrence, the mean activity and fibrosis scores were significantly lower in the SRL group. Donor age and acute rejection episodes were the only factors affecting the HCV recurrence rate (expB 1.02 [95% CI 1.01 to 1.03]); P=0.03; and expB 2.8 [95% CI 1.8 to 4.3]; P<0.01], respectively). SRL treatment did not alter patient survival rates. Among patients treated with SRL-based immunosuppression, higher drug area under the curve levels were associated with a trend to lower disease activity and fibrosis at diagnosis; however, higher SRL levels were associated with shorter recurrence-free survival (P=0.038).

CONCLUSION

Results of the present analysis suggest that de novo SRL-based immunosuppression can be safely used in patients undergoing LT for HCV-associated liver disease; however, SRL-based immunosuppression did not significantly affect the timing or severity of post-transplant HCV recurrence. HCV recurrence in SRL-treated patients had lower progressive activity and fibrosis levels on serial biopsy.     

Management of telaprevir-based triple therapy for hepatitis C virus recurrence post liver transplant

AIM: To characterize management of telaprevir (TVR)-based triple therapy of hepatitis C virus (HCV) reinfection after liver transplantation (LT).METHODS: We retrospectively analyzed safety and efficacy of telaprevir - based triple therapy in a single center cohort of 19 patients with HCV genotype (GT) 1 recurrence after LT, with respect to factors possibly predicting sustained viral response (SVR) or non-SVR. All patients were treated with TVR, pegylated (PEG) and ribavirine (RBV) for 12 wk followed by a dual phase with PEG/RBV for 12 wk in 7 patients and for 36 wk in 5 patients.RESULTS: In total 11/19 (58%) of patients achieved a sustained response. All (11/11) SVR patients showed a rapid viral response at treatment weeks 4 and 11/14 rapid virological response (RVR) patients achieved SVR. Notably, all (7/7) patients who completed 48 wk of therapy and 80% (4/5) patients who completed 24 wk of therapy achieved SVR24. Treatment failure was significantly (P > 0.049) more frequent in GT1a infection (5/7) compared to GT1b (3/12) infection and was associated with emergence of resistance-associated mutations in the NS3 protease domain. Bilirubin level at baseline is also related to SVR (P > 0.030). None of the patients had to discontinue treatment due to side effects.CONCLUSION: RVR, GT and bilirubin are clearly related to achievement of SVR. Providing a thorough patient selection and monitoring, a full course of TVR-based triple therapy in LT patients is feasible and achieves high SVR rates.