慢性丙型肝炎抗病毒治疗专家共识

干扰素治疗开创了丙型肝炎抗病毒治疗时代。聚乙二醇化干扰素（pegylated interferon,Peg—IFN）联合利巴韦林（ribavirin,RBV）是目前慢性丙型肝炎（chronic hepatitis C,CHC）抗病毒治疗的标准方案,约65％患者可取得持续病毒学应答（sustained virological response,SVR）。近年来,应答指导治疗（response-guided therapy,RGT）、特殊患者的治疗以及抗病毒治疗不良反应的处理均取得迅速进展。《中华实验和临床感染病杂志（电子版）》编辑部与《中国肝脏病杂志（电子版）》编辑部组织国内部分专家对相关资料进行整理与分析,综合专家意见,形成了《慢性丙型肝炎抗病毒治疗专家共识》（以下简称《共识》）。     

Immune‐mediated graft dysfunction in liver transplant recipients with hepatitis C virus treated with direct‐acting antiviral therapy

Interferon treatment of hepatitis C virus (HCV) infection after liver transplantation (LT) can result in immune‐mediated graft dysfunction (IGD). The occurrence of, risk factors for, and outcomes of IGD with direct‐acting antiviral (DAA) therapy have not been reported. We conducted a multicenter study of HCV+LT recipients who did or did not develop DAA‐IGD (1 case: 2 controls—33 vs 66). Among all treated between 2014 and 2016, DAA‐IGD occurred in 3.4% (33/978). IGD occurred only after treatment completion (76.0 [IQR, 47.0;176]). Among those treated, 48% had plasma cell hepatitis, 36% acute cellular rejection, 6% chronic rejection, and 9% combined findings. Median time to liver enzyme resolution was 77.5 days (IQR, 31.5;126). After diagnosis, hospitalizations, steroid‐induced hyperglycemia, and infection occurred in a higher percentage of cases vs controls (33% vs 7.5%, 21% vs 1.5%, 9% vs 0%; all P < .05). Only one IGD patient died and none required retransplant. A multivariate regression analysis found that liver enzyme elevations during and soon after DAA therapy completion correlated with subsequent IGD. In conclusion, while DAA‐IGD is uncommon, liver enzyme elevations during or after DAA therapy may be a sign of impending IGD. These indicators should guide clinicians to diagnose and treat IGD early before the more deleterious later clinical presentation.     

Anemia in liver transplant recipients undergoing antiviral treatment for recurrent hepatitis C.

Adherence to antiviral therapy is essential to achieve sustained virological responses in patients treated for hepatitis C. An important limitation to use of appropriate doses of ribavirin is development of anemia. The aim of this study is to identify risk factors associated with anemia in liver transplant recipients undergoing treatment for recurrent hepatitis C virus (HCV). Retrospective analysis was performed on 115 adult liver transplantation (LT) recipients who received antiviral treatment. Anemia was defined as hemoglobin of <10 gm/dL or the use of erythropoietin replacement therapy. Variables found to be significant in univariate analysis were further studied in multivariate analysis. The mean (+/- standard deviation [SD]) age of our cohort was 52.1 (+/- 8.8) yr. Anemia developed in 44 patients (38.3%). Mean (+/- SD) onset of anemia was 8.9 (+/- 6.8) weeks after initiation of antiviral therapy. A total of 30 patients (26%) required erythropoietin replacement, at a mean (+/- SD) of 7.9 (+/- 6.0) weeks after start of antiviral treatment. A total of 27 patients (24%) required ribavirin dose reduction, at a mean (+/- SD) time to dose reduction of 8.1 (+/- 6.3) weeks. In univariate analysis, body mass index (BMI) (P < 0.01), mycophenolate mofetil use (P = 0.05), trimethoprim-sulfamethoxazole (P = 0.02), and age (P = 0.02) were statistically significant. In conclusion, in multivariate analysis, BMI (P < 0.01) and age (P = 0.02) were found to be independent predictors of anemia. Anemia is common in liver transplant recipients treated for recurrent HCV. Special vigilance is required for older patients and patients with a low BMI.     

丙型肝炎病毒基因型和抗病毒治疗病毒学应答的相关性研究

目的探讨慢性丙型肝炎病毒（HCV）感染者病毒基因型对聚乙二醇化干扰素联合利巴韦林抗病毒治疗病毒学应答的影响。方法采用PCR产物直接测序法检测71例HCV感染者的HCV基因型。所有患者接受聚乙二醇化干扰素皮下注射,联合口服利巴韦林抗病毒治疗。分析HCV基因型对快速病毒学应答（RVR）、早期病毒学应答（EVR）、治疗结束时病毒学应答（ETVR）和持续病毒学应答（SVR）的影响。结果71例患者中,HCV基因1b型48例,占67.6%;2a型12例,占16.9%;3a型6例,占8.5%;3b型2例,占2.8%;6a型1例,占1.4%;未分型2例,占2.8%。治疗4周时,基因1型组和非1型组的RVR分别为27.1%和87.0%,差异具有统计学意义（χ2=22.4076,P=0.000002）。治疗12周时,基因1型组和非1型组的EVR分别为39.6%和13.0%,差异有统计学意义（χ2=5.1216,P=0.02363）。疗程结束时,基因1型组和非1型组的ETVR分别为68.8%和100%,差异无统计学意义（χ2=2.9520,P=0.08577）。已停药随访24周的患者出现SVR者,基因1型组、非1型组分别为62.22%和100%,差异具有统计学意义（χ2=8.3797,P=0.00379）。结论我国HCV感染者基因型以1b型和2a型为主。基因1型HCV感染者的RVR、EVR和SVR均低于非基因1型者。     

Fibrosis progression in hepatitis C positive liver recipients after sustained virologic response to antiviral combination therapy (interferon-ribavirin therapy)

The rate of fibrosis progression was analyzed in 28 hepatitis C virus-infected liver graft recipients showing sustained virologic response after treatment with ribavirin plus either standard interferon alpha-2b (n=8), pegylated interferon alpha-2b (n=8), or pegylated interferon alpha-2a (n=12). Protocol biopsies before treatment as well as one, three, and five years after treatment showed no significant increase in mean fibrosis scores within the first three years after treatment (mean score at baseline 1.8 and at one and three years 2.0 and 2.1, respectively). Five years after cessation of treatment, the mean fibrosis score declined to 1.4 (P=0.2). Six of 28 patients (21%) showed an increase in fibrosis, five (18%) a decrease, and 17 (60%) no changes. The yearly fibrosis progression rate was 0.75 before treatment and 0.15 after antiviral treatment. Sustained virologic response is associated with a deceleration of fibrosis progression and might therefore play a major role in prevention of graft cirrhosis in hepatitis C virus-infected liver graft recipients.     

Influence of hepatitis C on renal function after liver transplantation

Liver transplantation (OLT) is often complicated by renal failure. Hepatitis C (HCV) is said to be a risk factor for renal failure after OLT, but few studies have analyzed this directly. We evaluated all patients who received a liver transplant from 1995 through 2003. There were 147 patients infected with HCV and 202 not infected. Patients with HCV were further divided into 114 patients with benign HCV and 33 patients with severe HCV defined by bridging fibrosis or cirrhosis. The groups were evaluated for the development of renal insufficiency defined as a creatinine above 1.8 mg/dL on three consecutive occasions or renal failure as defined by the need for dialysis or renal transplant. The incidence of renal failure in patients with HCV was 10.2% and in patients without HCV was 3.5% (P = .004). Patients with severe HCV had an incidence of 12.1% vs 9.7% for patients with mild HCV. The linear trend in renal failure from non-HCV to mild HCV to severe HCV was significant (P = .012). The incidence of renal insufficiency was 23.4% in patients with HCV and 14.9% in patients without HCV (P = .080). The incidence was 32.3% in patients with severe HCV and 20.6% in patients with mild HCV. The trend in renal insufficiency across the three groups was mildly significant (P = .042). On multivariate analysis, HCV was a risk factor for renal failure with a relative risk of 2.58 (P = .045). The study suggests that HCV and the severity of recurrent HCV are risk factors for renal dysfunction after liver transplantation.     

Liver transplantation and hepatitis C virus: systematic review of antiviral therapy

Antiviral therapy for recurrent hepatitis C after liver transplantation is increasingly used. This systematic review presents both viral and histological response in three areas: pretransplant (5 studies/180 patients), preemptive therapy soon after transplant (10 studies/417 patients), and therapy for established disease (75 studies/2027 patients). There were only 16 randomized studies (543 patients). Significant dose reductions and drug stoppage rates occurred. The data on histological improvement and risk of rejection are conflicting. Even the best antiviral therapy (pegylated interferon/ribavirin) is neither easily used nor reasonably effective. The best strategy will be pretransplant treatment, most likely with newer agents.     

Preemptive antiviral treatment for hepatitis C virus after living donor liver transplantation

Background

Recurrence following liver transplantation for hepatitis C virus (HCV), which is universal, affects long-term outcomes. Treatment with interferon (IFN) and ribavirin (RBV), the only widely available options at this time, have been faced with low tolerability and overall unsatisfactory results in deceased donor liver transplantation (DDLT). However, its place after living donor liver transplantation (LDLT) remains a matter of debate. Since most LDLT cases are performed in a planned manner at a lower Model for End-stage Liver Disease (MELD) score compared to DDLT, we have aggressively applied preemptive INF/RBV in our series.

Patients and methods

We studied 122 adult recipients who underwent LDLT for HCV-related end-stage liver disease. The preemptive IFN/RBV protocol initiated treatment promptly after improvement in the patient's general condition with a low-dose IFN alpha2b and RBV (400 mg/d) followed by a gradual increase in the INFalpha2b dosage. Finally, we applied pegylated IFN (1.5 ug/kg/wk) and RBV (800 mg/d). The treatment was continued for 12 months after serum HCV-RNA became negative, which was defined as the end-of-treatment response (ETR). The response was considered to be a sustained viral response (SVR) if there were negative serologic results without antiviral treatment for another 6 months. Splenectomy was performed at the time of LDLT to improve tolerability to INF/RBV. The median age of the patients was 55 yrs (range = 23-66), with male dominance (87 males and 35 females). Median MELD score was 14 (range = 6-48). The series included 72 patients with hepatocellular carcinomas, and six with HIV coinfections. In 98 cases, HCV genotype was 1b.

Results

Overall survival at 5 years was 79%. Cumulative response rates under the protocol were ETR 56% and SVR 44% at 5 years.

Conclusions

Preemptive IFN/RBV therapy after LDLT for HCV is feasible with acceptable outcomes.     

Efficacy, predictors of response, and potential risks associated with antiviral therapy in liver transplant recipients with recurrent hepatitis C.

There are unresolved issues regarding sustained virological response (SVR), tolerance and risk of rejection following antiviral therapy in liver transplantation (LT). The aim of our study was to determine efficacy, rejection risk and factors associated with SVR. HCV-infected LT patients with at least 6 months of follow-up following end-of-therapy (EOT) received combination therapy of ribavirin (Rbvr) + standard (n = 31)/pegIFN (n = 36) between 1999 and 2004 (95% genotype 1). An EOT and SVR was obtained in 46% and 33%, respectively. Type of antiviral therapy, use of erythropoietin, compliance, and early virologic response (EVR) were predictive of SVR, but only the latter remained in the multivariate analysis. Premature discontinuation, not impacted by the use of erythropoietin or GCSF, occurred in 40% patients. None of the variables predicted rejection (acute n = 2, chronic n = 4). A SVR occurred in 3/4 patients with chronic rejection. In conclusion, the efficacy of pegIFN-Rbvr is similar to the non-transplant population. An EVR at 3 months is useful to predict lack of response. The type of calcineurin inhibitor and history of prior non-response to IFN before LT do not influence the outcome of therapy. Severe rejection may lead to graft loss, a complication difficult to predict.     

Impact of the recurrence of hepatitis C virus infection after liver transplantation on the long-term viability of the graft.

BACKGROUND: The impact of hepatitis C virus (HCV) infection recurrence after orthotopic liver transplantation (OLT) on graft viability is still not accurately defined. Our study aims to evaluate the magnitude and rate of progression of HCV-induced liver damage after OLT in a single institution cohort of 122 HCV-infected recipients. METHODS: All patients transplanted at our institution between 1988 and 1996 with positive serum HCV antibodies before OLT, minimum postoperative survival of 6 months, and without hepatitis B virus coinfection or severe non-HCV-related graft complications were retrospectively included in the study. RESULTS: HCV infection recurrence was almost universal, and genotype 1b was observed in 87% of the cases. After a median histological follow-up of 43 months (range: 7-96), evidences of HCV-induced histological damage were found in 94% of the cases. The actuarial rates of severe graft damage (including cirrhosis, fibrosing cholestatic hepatitis, and submassive liver necrosis) were 15%, 33%, and 44% at 3, 5, and 7 years, respectively, and among these patients, 52% developed decompensated liver disease during the follow-up and 36% lost their grafts. The biochemical severity at the onset of the recurrent hepatitis and the development of cholestasis or cytomegalovirus disease were independent predictors of severe HCV-related graft damage. No differences were found in graft and patient survival when positive-HCV OLT recipients were compared with a coetaneous cohort of 215 non-HCV OLT recipients. CONCLUSIONS: HCV infection recurrence leads to severe liver damage and subsequently to clinical decompensation in a significant proportion of OLT recipients. Some clinical and biochemical characteristics can predict the severity of HCV-induced graft damage.     

乙肝病毒因素对肝癌肝切除及肝移植术后复发的影响

肝切除术是目前公认的治疗肝癌的首选方式,但术后肿瘤复发率较高.中国肝癌患者多数合并乙肝感染,乙肝病毒(HBV)因素如:病毒基因型、血清e抗原状态、血清HBV DNA水平、肝内HBV DNA水平与肝切除术后肿瘤复发相关.抗病毒治疗,尤其是干扰素治疗可能是预防肝癌复发的有效方式之一.乙肝病毒因素也可影响肝移植术后患者复发率.     

Response to antiviral therapy in liver transplant recipients with recurrent hepatitis C viral infection: a single center experience

Jain A, Sharma R, Ryan C, Safadjou S, Kashyap R, Mantry P, Maliakkal B, Orloff M. Response to antiviral therapy in liver transplant recipients with recurrent hepatitis C viral infection: a single center experience.
Clin Transplant 2010: 24: 104–111. © 2009 John Wiley & Sons A/S.   Abstract: 
Introduction:  Recurrence of hepatitis C virus (HCV) in hepatic allograft is a major concern after successful liver transplant (LTx).
Aim:  To examine the response rate to pegylated interferon (PEG–IFN) and ribavirin in post-LTx patients with HCV recurrence.
Patients and methods:  Between January 2003 and September 2006, 60 patients with biopsy proven HCV recurrence (46 males and 14 females) received PEG–IFN 2a (n = 40) or IFN 2b (n = 20) with ribavirin. All patients were followed until July 2007.
Results:  Fourteen patients (23.3%) tolerated antiviral therapy for less than six months and 10 (16.7%) discontinued therapy between six and 11 months. PEG–IFN dose was reduced in 21 (35%) patients and ribavirin dose was reduced in 16 (26.7%) patients. Overall, 55% patients achieved end of treatment response (EOT) and 35% sustained virological response (SVR). Mean Hepatitis Activity Index and Fibrosis Score pre-therapy was 5.8 ± 1.9 and 1.7 ± 1.3 and post-therapy, it was 4.4 ± 2.1 and 2.4 ± 1.6, respectively. Overall, three yr patient and graft survival was 73.9% and 69.2%, respectively. The patients with SVR had significantly lower viral load compared with other groups (p = 0.028).
Conclusion:  PEG–IFN and ribavirin therapy achieved 55% EOT and 35% SVR; 60% patients tolerated therapy. Biochemical response was observed in all groups of patients irrespective of virological response.     

慢性乙型肝炎抗病毒治疗专家共识

自2005年12月中国《慢性乙型肝炎防治指南》发布以来,国内外对于乙型肝炎病毒（HBV）及其相关慢性肝病的研究不断深入。亚太肝脏学会（APASL）、欧洲肝脏学会（EASL）及美国肝脏病学会（AASLD）陆续发布了各自更新的慢性乙型肝炎（CHB）临床指南及共识。     

慢性乙型重型肝炎抗病毒治疗的研究进展

目前,慢性重型乙型肝炎已成为导致乙型肝炎患者死亡的主要原因,病死率国外为80%～90%,国内为50%～78%[1].近年来,慢性重型乙型肝炎患者的抗病毒治疗取得了较大进展,现将相关研究结果作一综述.