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].     

小分子化合物抗病毒治疗丙型肝炎肝硬化

正直接抗病毒药物(direct-acting antiviral agents,DAAs)对丙型肝炎的治疗效果已取得突破性进展,持续病毒学应答(sustained virologic response,SVR)高达90%~95%~([1])。目前,DAAs主要包括NS3/4A蛋白酶抑制剂、核苷类NS5B聚合酶抑制剂、非核苷类NS5B聚合酶抑制剂、NS5A抑制剂。自     

Interferon-free regimens for the treatment of hepatitis C virus in liver transplant candidates or recipients

The goal of therapy in chronic hepatitis C virus (HCV) infection is sustained virological response (SVR) which reflects HCV eradication. Treatment against HCV has dramatically improved with the recent availability of direct-acting antivirals (DAAs) including sofosbuvir, simeprevir, daclatasvir, ledipasvir/sofosbuvir, paritaprevir/ombitasvir and dasabuvir. Carefully selected combinations of these DAAs offer the potential for highly effective all-oral safe regimens even for patients with decompensated cirrhosis or liver transplant (LT) recipients. Like all current protease inhibitors, simeprevir and paritaprevir should not be used in patients with Child C cirrhosis, while sofosbuvir and ledipasvir/sofosbuvir should not be given in patients with severe renal impairment and glomerular filtration rate less than 30 mL/min. Drug-drug interactions may still occur with the current DAAs particularly in post-LT patients, in whom simeprevir should not be co-administered with cyclosporine and dose adjustments of calcineurin inhibitors are required in case of regimens including the ritonavir boosted paritaprevir. Phase II clinical trials and real life cohort studies have shown that sofosbuvir based combinations are safe and can achieve improvements of clinical status, high SVR rates and even prevention of post-LT HCV recurrence in patients with decompensated cirrhosis or LT-candidates. In the post-LT setting, sofosbuvir based regimens and the combination of paritaprevir/ombitasvir and dasabuvir have been reported to be safe and achieve high SVR rates, similar to those in non-transplant patients, being effective even in cases with cholestatic fibrosing hepatitis. Ongoing clinical trials and rapidly emerging real life data will further clarify the safety and efficacy of the new regimens in these settings.     

我国丙型肝炎肝硬化患者DAA治疗现状及短期预后的研究

目的了解丙型肝炎肝硬化患者直接抗病毒药物(DAA)治疗现状、短期预后和影响因素。方法选取2015年1月至2019年11月期间于瑞金医院感染科诊治的丙型肝炎肝硬化患者,收集其数据,研究基线特征、DAA方案及疗效和预后的关系。结果共入组161例,DAA治疗者149例;代偿组122例,失代偿组27例;两组在年龄、性别、HCV基因型及干扰素治疗史等方面无显著性差别;两组疗效与安全性均良好,其中SVR12率(99.17%比96.25%,P=0.325)和SVR24率(96.64%比92.0%,P=0.614)均无明显差异;基线肝硬化失代偿期患者中发生肝病进展的比例明显高于代偿期患者(50%vs.13.75%,P=0.000);基线肝硬化失代偿是DAA治疗后短期预后的独立危险因素(HR 6.765,95%Cl:2.866~15.969,P=0.000)。结论基线肝硬化失代偿是DAA治疗后短期预后的独立预测因素。     

Direct-Acting Antiviral Therapy for Hepatitis C Virus in Patients with BCLC Stage B/C Hepatocellular Carcinoma

Background: The benefits of hepatitis C virus (HCV)eradication for hepatocellular carcinoma (HCC) patients in Barcelona Clinic Liver Cancer (BCLC) stage B/C remain uncertain. Methods: In this hospital-based cohort study, all HCV-infected patients with BCLC stage B/C HCC during the period January 2017 to March 2021 were retrospectively screened, with 97 patients who had completed direct-acting antiviral (DAA) therapy being enrolled for final analysis. Results: In total, the sustained virological response (SVR) rate was 90.7%. In logistic regression analysis, progressive disease (PD) to prior tumor treatments was significantly associated with SVR failure (odds ratio 5.59, 95% CI 1.30–24.06, p = 0.021). Furthermore, the overall survival (OS) rate was significantly higher in the SVR group than that in the non-SVR group (1-year OS: 87.5% vs. 57.1%, p = 0.001). SVR was found to be an independent factor related to OS (hazard ratio 8.42, 95% CI 2.93–24.19, p = 0.001). However, even upon achieving SVR, the OS rates in BCLC stage C or Child–Pugh stage B patients remained poor. Conclusions: In BCLC stage B/C HCC, DAA could achieve a high SVR rate except in those patients with PD to prior HCC treatments. SVR was related to improvements in OS; therefore, DAA therapy should be encouraged for patients diagnosed without a short life expectancy.     

Epidemiology of hepatitis C virus infection in a country with universal access to direct‐acting antiviral agents: Data for designing a cost‐effective elimination policy in Spain

Accurate HCV prevalence estimates are necessary for guiding elimination policies. Our aim was to determine the HCV prevalence and assess the cost‐effectiveness of a screen‐and‐treat strategy in the Spanish population. A population‐based, cross‐sectional study (PREVHEP‐ETHON Cohort, Epidemiological sTudy of Hepatic infectiONs; NCT02749864) was performed from July 2015‐April 2017. Participants from three Spanish regions were selected using two‐stage conglomerate sampling, and stratified by age, with randomized subject selection. Anthropometric and demographic data were collected, and blood samples were taken to detect anti‐HCV antibodies/quantify HCV RNA. The cost‐effectiveness of the screening strategies and treatment were analysed using a Markov model. Among 12 246 participants aged 20‐74 (58.4% females), the overall anti‐HCV prevalence was 1.2% (95% CI 1.0‐1.4), whereas the detectable HCV‐RNA prevalence was 0.3% (0.2‐0.4). Infection rates were highest in subjects aged 50‐74 years [anti‐HCV 1.6% (1.3‐1.9), HCV RNA 0.4% (0.3‐0.6]. Among the 147 anti‐HCV + subjects, 38 (25.9%) had active infections while 109 (74.1%) had been cleared of infection; 44 (40.4%) had cleared after antiviral treatment, whereas 65 (59.6%) had cleared spontaneously. Overall, 59.8% of the anti‐HCV + participants were aware of their serological status. Considering a cost of treatment of €7000/patient, implementing screening programmes is cost‐effective across all age cohorts, particularly in patients aged 50‐54 (negative incremental cost‐effectiveness ratio which indicates a cost‐saving strategy). The current HCV burden is lower than previously estimated, with approximately 25% of anti‐HCV + individuals having an active infection. A strategy of screening and treatment at current treatment prices in Spain is cost‐effective across all age cohorts.     

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。     

A different perspective on sofosbuvir‐ledipasvir treatment of patients with HCV genotype 1b cirrhosis: The ital‐c network study

The effectiveness of a 12‐week course of sofosbuvir‐ledipasvir in treatment‐experienced HCV genotype 1b‐infected patients with cirrhosis is still under debate. Our primary endpoint was to compare the sustained virological response at post‐treatment week 12 (SVR12) of sofosbuvir‐ledipasvir in combination with ribavirin for 12 weeks, and sofosbuvir‐ledipasvir alone for 24 weeks. This was a prospective observational study that enrolled 424 (195 naive, 229 experienced; 164 treated for 12 weeks with Ribavirin and 260 with sofosbuvir‐ledipasvir alone for 24 weeks) consecutive HCV genotype 1b‐infected patients with cirrhosis. The SVR12 rates were 93.9% and 99.2% in patients treated for 12 and 24 weeks, respectively (P = .002). The baseline characteristics of patients treated for 12 weeks were significantly different from those treated for 24 weeks as regards their younger age (P = .002), prevalence of Child‐Pugh class A (P = .002), lower MELD scores (P = .001) and smaller number of nonresponders (P = .04). The shorter treatment was significantly associated with a lower SVR12 in univariate and multivariate analyses (P = .007 and P = .008, respectively). The SVR rate was unaffected by age, gender, BMI, Child‐Pugh class, MELD score or previous antiviral treatment. Patients receiving ribavirin experienced more episodes of ascites and headache but less recurrence of hepatocellular carcinoma (HCC), and were prescribed more diuretics and cardiopulmonary drugs. No patient discontinued treatment. The therapeutic regimen of sofosbuvir‐ledipasvir plus ribavirin administered for 12 weeks was less effective than sofosbuvir‐ledipasvir alone given for 24 weeks. At odds with European guidelines, the recommended 12‐week treatment with sofosbuvir‐ledipasvir alone might be suboptimal for this setting of patients.     

丙型肝炎肝硬化抗病毒治疗现状

目前干扰素联合利巴韦林是慢性HCV感染的主要抗病毒治疗方案,但丙型肝炎肝硬化患者对于抗病毒治疗耐受性差.目前研究报道对于丙型肝炎肝硬化患者进行抗病毒治疗,如能获得持续病毒学应答(SVR),有利于缓解肝纤维化进展,并减少肝移植术后HCV再感染的发生.因此,应对丙型肝炎肝硬化患者进行仔细评估,对于进行抗病毒治疗的患者可给予适当干预以维持抗病毒治疗的进行,并在治疗过程中密切监测不良反应的发生.     

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.     

The optimal timing of hepatitis C therapy in liver transplant‐eligible patients: Cost‐effectiveness analysis of new opportunities

Different strategies of DAAs treatment are currently possible both pre‐ and postliver transplantation (LT). Clinical and economic consequences of these strategies still need to be adequately investigated; this study aims at assessing their cost‐effectiveness. A decision analytical model was created to simulate the progression of HCV‐infected patients listed for decompensated cirrhosis (DCC) or for hepatocellular carcinoma (HCC). Three DAAs treatment strategies were compared: (i) a 12‐week course of DAAs prior to transplantation (PRE‐LT), (ii) a 4‐week course of DAAs starting at the time of transplantation (PERI‐LT) and (iii) a 12‐week course of DAAs administered at disease recurrence (POST‐LT). The population was substratified according to HCC presence and, in those without HCC, according to the MELD score at listing. Data on DAAs effectiveness were estimated using a cohort of patients still followed by 11 transplant centres of the European Liver and Intestine Transplant Association and by data available in the literature. In this study, PRE‐LT treatment strategy was dominant for DCC patients with MELD<16 and cost‐effective for those with MELD16‐20, while POST‐LT strategy emerged as cost‐effective for DCC patients with MELD>20 and for those with HCC. Sensitivity analyses confirmed PRE‐LT as the cost‐effective strategy for patients with MELD≤20. In conclusion, PRE‐LT treatment is cost‐effective for patients with MELD≤20 without HCC, while treatments after LT are cost‐effective in cirrhotic patients with MELD>20 and in those with HCC. It is worth reminding, though, that the final choice of a specific regimen at the patient level will have to be personalized based on clinical, social and transplant‐related factors.     

Similar recovery of liver function after response to all‐oral HCV therapy in patients with cirrhosis with and without HIV coinfection

Among patients with cirrhosis, recovery of liver function after SVR to all‐oral direct‐acting antivirals (DAA) in HIV/HCV coinfection could be different to that in HCV monoinfection. Because of this, we compared the changes in several markers of liver function between HCV‐monoinfected and HIV/HCV‐coinfected patients with cirrhosis who achieved SVR12 to DAA combinations. In this retrospective cohort study, cirrhotics included in the HEPAVIR‐DAA and GEHEP‐MONO cohorts were selected if they had SVR12 to all‐oral DAAs. Patients treated with atazanavir were excluded. Liver function improvement was defined as Child‐Pugh‐Turcotte (CPT) decrease ≥1 and/or MELD decrease ≥2 between baseline and SVR12. Liver function worsening was defined as a CPT increase ≥1 and/or MELD increase ≥2 and/or decompensations between baseline and SVR12. We included 490 patients, 270 (55%) of them with HIV coinfection. Liver function improved in 50 (56%) HCV‐infected individuals and in 82 (57%) HIV/HCV‐coinfected patients (P = 0.835). Liver function worsened in 33 (15%) HCV‐monoinfected patients and in 33 (13%) HIV/HCV‐coinfected patients (P = 0.370). Factors independently related with liver function improvement were male gender [adjusted OR (AOR) 2.1 (95% confidence interval, 95% CI: 1.03‐4.2), P = 0.040], bilirubin < 1.2 mg/dL (AOR 1.8 [95% CI: 1.004‐3.3], P = 0.49), and INR < 1.3 (AOR 2.4 [95% CI: 1.2‐5.0], P = 0.019) at baseline. After multivariate analysis, albumin < 3.5 g/dL was associated with liver function worsening (AOR 6.1 [95% CI: 3‐12.5], P < 0.001). Liver function worsening and improvement rates after responding to DAA are similar among HCV‐monoinfected and HIV/HCV‐coinfected cirrhotics. Gender, INR, bilirubin, and albumin levels were associated with liver function changes after response to DAAs.     

阿德福韦酯治疗慢性乙型肝炎、肝硬化代偿期和失代偿期患者2年疗效比较

目的观察慢性乙型肝炎（乙肝）、乙肝肝硬化代偿期和失代偿期患者接受阿德福韦酯（ADV）抗病毒治疗2年的疗效。方法对初治的慢性乙肝32例（慢性乙肝组）、乙肝肝硬化代偿期10例（肝硬化代偿期组）和失代偿期14例（肝硬化失代偿期组）应用ADV治疗2年,治疗前和治疗后每3个月检测Au等生化指标及HBVDNA等病毒学指标。结果3组患者在治疗前各项指标基线水平无显著差异,具有可比性。ADV治疗1年和2年时,3组ALT的复常率和HBeAg血清学转换率之间差异无统计学意义（P〉0．05）。治疗2年时慢性乙肝组HBVDNA水平下降的中位数为5．9log10 U／ml,肝硬化代偿期组为6．2log10 U／ml,肝硬化失代偿期组为2．9log U／ml。肝硬化失代偿期组在治疗6个月后的病毒学应答比慢性乙肝组和肝硬化代偿期组差。结论接受ADV治疗2年的慢性乙肝、肝硬化代偿期和失代偿期患者中,肝硬化失代偿期患者病毒学应答差。     

Safety and efficacy of coblopasvir and sofosbuvir in patients with genotypes 1, 2, 3 and 6 HCV infections without or with compensated cirrhosis

A simple, pangenotypic and effective treatment regimen for patients with a broad range of chronic hepatitis C virus (HCV) infections remains an unmet medical need. We conducted a phase 2, randomized, open study involving untreated patients with chronic HCV genotypes 1, 2, 3, or 6 infections. Patients without cirrhosis were randomly assigned in a 1:2 ratio to receive capsules of the NS5A inhibitor coblopasvir at a dose of 30 or 60 mg plus tablets of the nucleotide polymerase inhibitor sofosbuvir (400 mg) once daily for 12 weeks. Patients with cirrhosis received 60 mg coblopasvir plus sofosbuvir for 12 weeks. The primary endpoint was the sustained virologic response at 12 weeks after the end of therapy (SVR12). Of the 110 patients who were enrolled in the study, 59 were male, 62.7% had HCV genotype 1, 24.5% had genotype 2, 6.4% had genotype 3, and 6.4% had genotype 6. The average age was 45.5 years. A total of 10.9% of patients had compensated cirrhosis. The rate of SVR12 was 98.2% in the intention‐to‐treat (ITT). One genotype 6 patient with cirrhosis experienced virologic relapse. One genotype 2 patient without cirrhosis failed to complete the follow‐up and quit the study. Serious adverse events (SAEs) were reported in 2 patients and were not related to coblopasvir and sofosbuvir. Most adverse events (AEs) did not require treatment. Coblopasvir plus sofosbuvir taken once daily for 12 weeks provided high rates of sustained virologic response (SVR) and had a good safety profile among patients with HCV genotypes 1, 2, 3, or 6 infections, including those with compensated cirrhosis.     

New approaches in the treatment of hepatitis C

About 130-170 million people, is estimated to be infected with the hepatitis C virus(HCV). Chronic HCV infection is one of the leading causes of liverrelated death and in many countries it is the primaryreason for having a liver transplant. The main aim of antiviral treatment is to eradicate the virus. Until a few years ago the only treatment strategy was based on the combination of pegylated interferon and ribavirin(PEG/RBV). However, in genotypes 1 and 4 the rates of viral response did not surpass 50%, reaching up to 80% in the rest. In 2011 approval was given for the first direct acting antiviral agents(DAA), boceprevir and telaprevir, for treatment of genotype 1, in combination with traditional dual therapy. This strategy managed to increase the rates of sustained viral response(SVR) in both naive patients and in retreated patients, but with greater toxicity, interactions and cost, as well as being less safe in patients with advanced disease, in whom this treatment can trigger decompensation or even death. The recent, accelerated incorporation since 2013 of new more effective DAA, with pan-genomic properties and excellent tolerance, besides increasing the rates of SVR(even up to 100%), has also created a new scenario: shorter therapies, less toxicity and regimens free of PEG/RBV. This has enabled their almost generalised applicability in all patients. However, it should be noted that most of the scientific evidence available is based on expert opinion, case-control series, cohort studies and phase 2 and 3 trials, some with a reduced number of patients and select groups. Few data are currently available about the use of these drugs in daily clinical practice, particularly in relation to the appearance of side effects and interactions with other drugs, or their use in special populations or persons with the less common genotypes. This situation suggests the need for the generalised implementation of registries of patients receiving antiviral therapy. The main inconvenience of these new drugs is their high cost. This necessitates selection and prioritization of candidate patients to receive them, via strategies established by the various national organs, in accordance with the recommendations of scientific societies.     

HBV和HCV相关肝硬化的抗病毒治疗

肝硬化患者抗病毒治疗的必要性和可行性备受关注。综述近年相关指南/共识和循证医学资料,介绍HBV和HCV相关肝硬化抗病毒治疗的适应证、治疗策略、药物选择及治疗收益/风险等方面的进展。资料显示,无论乙型肝炎还是丙型肝炎肝硬化,成功的治疗均可抑制病毒复制,改善病情,延缓疾病进展,延长生存期,减少并发症发生,并为相关肝细胞癌的外科和微创手术创造条件。因核苷和核苷酸类药物安全性好,推荐乙型肝炎肝硬化(包括失代偿期甚至出现并发症)患者尽早使用;而干扰素不良反应多,丙型肝炎肝硬化抗病毒较乙型肝炎困难,须慎重选择适应证。规范抗病毒方案对治疗肝硬化非常重要。