直接抗病毒药物治疗慢性丙型肝炎肝硬化的回顾性分析

目的:探讨直接抗病毒药物(direct-acting antiviral agent,DAA)治疗慢性丙型肝炎肝硬化患者实现持续病毒学应答(sustained virologic response, SVR)后的预后及转归。方法:回顾性分析2014年1月至2017年6月于天津市第二人民医院临床诊断为慢性丙型肝炎肝硬化的...     

Severe adverse events during antiviral therapy in hepatitis C virus cirrhotic patients: A systematic review

AIM: To identify severe adverse events (SAEs) leading to treatment discontinuation that occur during antiviral therapy in hepatitis C virus (HCV)-infected cirrhotic patients.METHODS: We identified all the articles published prior to December 2011 in the PubMed, Medline, Lilacs, Scopus, Ovid, EMBASE, Cochrane and Medscape databases that presented these data in cirrhotic patients. These studies evaluated the rate of SAEs leading to discontinuation of standard care treatment: Pegylated interferon (PegIFN) alpha 2a (135-180 μg/wk) or PegIFN alpha 2b (1 or 1.5 μg/kg per week) and ribavirin (800-1200 mg/d). Patients with genotype 1 + 4 underwent treatment for 48 wk, whereas those with genotypes 2 + 3 were treated for 24 wk.RESULTS: We included 17 papers in this review, comprising of 1133 patients. Treatment was discontinued due to SAEs in 14.5% of the patients. The most common SAEs were: severe thrombocytopenia and/or neutropenia (23.2%), psychiatric disorders (15.5%), decompensation of liver cirrhosis (12.1%) and severe anemia (11.2%). The proportion of patients who needed to discontinue their therapy due to SAEs was significantly higher in patients with Child-Pugh class B and C vs those with Child-Pugh class A: 22% vs 11.4% (P = 0.003). A similar discontinuation rate was found in cirrhotic patients treated with PegIFN alpha 2a and those treated with PegIFN alpha 2b, in combination with ribavirin: 14.2% vs 13.7% (P = 0.96). The overall sustained virological response rate in cirrhotic patients was 37% (95%CI: 33.5-43.1) but was significantly lower in patients with genotype 1 + 4 than in those with genotype 2 + 3: 20.5% (95%CI: 17.9-24.8) vs 56.5% (95%CI: 51.5-63.2), (P < 0.0001).CONCLUSION: Fourteen point five percent of HCV cirrhotic patients treated with PegIFN and ribavirin needed early discontinuation of therapy due to SAEs, the most common cause being hematological disorders.     

Use of direct-acting antiviral agents in hepatitis C virus-infected liver transplant candidates

Since the advent of direct acting antiviral(DAA) agents, chronic hepatitis C virus(HCV) treatment has evolved at a rapid pace. In contrast to prior regimen involving ribavirin and pegylated interferon, these newer agents are highly effective, well-tolerated, have shorter course of therapy and safer essentially in all HCV patients including those with advanced liver disease and following liver transplantation. Clinicians caring for HCV-infected patients on the liver transplant(LT) waitlist are often faced with a dilemma whether to treat HCV infection before or after liver transplantation. Sustained virological response(SVR) rates following HCV treatment may improve hepatic function sufficiently enough to negate the need for LT in certain patients. On the other hand, the decrease in MELD without improvement in quality of life in certain patients may lead to delay or dropout from potentially curative LT surgery list. In this context, our review focuses on the approach to and optimal timing of DAA-based treatment of HCV infection in LT candidates in the peri-transplant period.     

Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein expression predicts disease severity in chronic hepatitis C patients

Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA⁺-M2BP) has recently been developed as a promising liver fibrosis glyco biomarker. We assessed its efficacy in evaluating liver disease severity in chronic hepatitis C (CHC) in Taiwan. The association between WFA⁺-M2BP and histological features was evaluated among those CHC patients underwent liver biopsy. We also aimed to clarify the factors determining the performance of WFA⁺-M2BP in CHC. A total of 229 CHC patients were consecutively recruited. The mean value of WFA⁺-M2BP in patients from F0 to F4 was 1.68, 2.23, 3.45, 3.48, 3.77 respectively (linear trend P = 0.008). Linear regression analysis revealed that alanine aminotransferase (odds ratio [OR]: 0.03, 95% confidence intervals [CI]: 0.02–0.05, P < 0.001), AST (OR: ?0.1, 95% CI: ?0.02 to ?0.01, P < 0.001), and liver fibrosis (OR: 0.30, 95% CI: 0.01–0.59, P = 0.043) were the independent factors correlated to serum WFA⁺-M2BP level. The optimal cutoff values of WFA⁺-M2BP for fibrosis stages F1, F2, F3, and F4 were 1.42, 1.61, 1.42, and 2.67, respectively. Multivariate analysis revealed that the platelet count (OR/CI: ?0.009/0.986–0.996, P = <0.001), r-glutamyl transferase (OR/CI: 0.007/1.000–1.013, P = 0.036), and WFA⁺-M2BP (OR/CI: 0.187/1.057–1.374, P = 0.005). We concluded that WFA⁺-M2BP is a competent noninvasive marker for liver fibrosis assessment in CHC patients.     

Antiviral therapies for chronic hepatitis C virus infection with cirrhosis

Patients who are infected with hepatitis C virus(HCV) and also have advanced fibrosis or cirrhosis have beenrecognized as "difficult-to-treat" patients during an era when peginterferon and ribavirin combination therapy is the standard of care. Recent guidelines have clearly stated that treatment should be prioritized in this population to prevent complications such as decompensation and hepatocellular carcinoma. Recent advances in the treatment of chronic hepatitis C have been achieved through the development of direct-acting antiviral agents(DAAs). Boceprevir and telaprevir are first-generation DAAs that inhibit the HCV NS3/4A protease. Boceprevir or telaprevir, in combination with peginterferon and ribavirin, improved the sustained virological response rates compared with peginterferon and ribavirin alone and were tolerated in patients with HCV genotype 1 infection without cirrhosis or compensated cirrhosis. However, the efficacy is lower especially in prior non-responders with or without cirrhosis. Furthermore, a high incidence of adverse events was observed in patients with advanced liver disease, including cirrhosis, in real-life settings. Current guidelines in the United States and in some European countries no longer recommend these regimens for the treatment of HCV. Next-generation DAAs include second-generation HCV NS3/4A protease inhibitors, HCV NS5 A inhibitors and HCV NS5 B inhibitors, which have a high efficacy and a lower toxicity. These drugs are used in interferon-free or in interferon-based regimens with or without ribavirin in combination with different classes of DAAs. Interferon-based regimens, such as simeprevir in combination with peginterferon and ribavirin, are well tolerated and are highly effective especially in treatmentnave patients and in patients who received treatment but who relapsed. The efficacy is less pronounced in nullresponders and in patients with cirrhosis. Interferonfree regimens in combination with ribavirin and/or two or more DAAs could be used for treatment-nave, treatment-experienced and even for interferon-ineligible or interferon-intolerant patients. Some clinical trials have demonstrated promising results, and have shown that the efficacy and safety were not different between patients with and without cirrhosis. There are also promising regimens for genotypes other than genotype 1. Interferonis contraindicated in patients with decompensated cirrhosis, and further studies are needed to establish the optimal treatment regimen for this population. In the future, interferon-free and ribavirin-free regimens with high efficacy and improved safety are expected for HCVinfected patients with advanced liver diseases.     

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     

Treatment of hepatitis C in compensated cirrhotic patients is equally effective before and after liver transplantation

AIM: To investigate differences in tolerability and response to treatment in compensated cirrhotic patients affected by hepatitis C virus (HCV) infection before and after liver transplantation. METHODS: Forty-three HCV non-liver transplanted (LT) cirrhotics (mean age 55 ± 8 years, 65.1% male, Child-Pugh-A, genotype 1-4: 65.1%, 2-3: 34.9%) and 17 LT recipients with recurrent HCV-related cirrhosis (mean age 57 ± 9 years, 88.2% male, Child-Pugh-A, genotype 1-4: 76.5%, 2-3: 23.5%) were included in the analysis from retrospective series. All patients received recombinant or pegylated interferon plus ribavirin at a standard dose and duration. Adverse events were recorded and classified according to the Common Terminology Criteria for Adverse Events. The mean duration of follow-up was of 4.3 ± 1.8 years after the end of the treatment. RESULTS: An early virological response (EVR) was achieved in 30/43 (69.8%) non-LT and in 8/17 (47.1%) LT cirrhotics, a sustained virological response (SVR) in 18/43 (41.9%) and 5/17 (29.4 %), respectively. No sta- tistical difference was observed in EVR and SVR rates between the two groups. Among HCV non-LT cirrhotics, 6/43 (13.9%) discontinued the treatment prematurely, 11.6% of them receiving ≤ 80% of treatment; 8/17 (47%) LT cirrhotics withdrew the treatment, 35.2% of them receiving ≤ 80% of treatment. If compared with LT-ones (P = 0.015), an higher risk of treatment discontinuation could affect LT cirrhotics, who undergo more frequently ≤ 80% of treatment (P = 0.05). None of the non-LT cirrhotics died after the end of the treatment. With no regards to the achievement of SVR, LT cirrhotic patients showed a reduced survival in respect to non-LT ones (87% at 1 year, 76% at 3 and 5 years after the end of treatment).CONCLUSION: HCV antiviral treatment is equally effective in compensated cirrhotics both before and after LT, which patients show a higher risk of premature treatment withdrawal and a reduced survival, independently of the achievement of SVR.     

Sustained virologic response to direct-acting antiviral agents predicts better outcomes in hepatitis C virus-infected patients: A retrospective study

BACKGROUND Direct-acting antiviral agents(DAAs) are extremely effective in eradicating hepatitis C virus(HCV) in chronically infected patients. However, the protective role of the sustained virologic response(SVR) achieved by second-and thirdgeneration DAAs against the onset of hepatocellular carcinoma(HCC) and mortality is less well established.AIM To examine the occurrence of HCC or death from any cause in a retrospectiveprospective study of patients treated with DAAs.METHODS Patients were enrolled from a tertiary academic hospital center for liver disease management that collects subject data mainly from northeastern Italy. The study was conducted in 380 patients(age: 60 ± 13 years, 224 males, 32% with cirrhosis)treated with DAAs with or without SVR(95/5%), with a median follow up of 58 wk(interquartile range: 38-117). The baseline anthropometric features, HCV viral load, severity of liver disease, presence of extra-hepatic complications, coinfection with HIV and/or HBV, alcohol consumption, previous interferon use, alphafetoprotein levels, and renal function were considered to be confounders.RESULTS The incidence rate of HCC in patients with and without SVR was 1.3 and 59 per100 person-years, respectively(incidence rate ratio: 44, 95%CI: 15-136, P 0.001).Considering the combined endpoint of HCC or death from any cause, the hazard ratio(HR) for the SVR patients was 0.070(95%CI: 0.025-0.194, P 0.001). Other independent predictors of HCC or death were low HCV viremia(HR: 0.808, P =0.030), low platelet count(HR: 0.910, P = 0.041), and presence of mixed cryoglobulinemia(HR: 3.460, P = 0.044). Considering SVR in a multi-state model,the independent predictors of SVR achievement were absence of cirrhosis(HR:0.521, P 0.001) and high platelet count(HR: 1.019, P = 0.026). Mixed cryoglobulinemia predicted the combined endpoint in patients with and without SVR(HR: 5.982, P = 0.028 and HR: 5.633, P = 0.047, respectively).CONCLUSION DAA treatment is effective in inducing SVR and protecting against HCC or death.A residual risk of HCC persists in patients with advanced liver disease or with complications, such as mixed cryoglobulinemia or renal failure.     

Decade of optimizing therapy with direct-acting antiviral drugs and the changing profile of patients with chronic hepatitis C

Chronic infection with the hepatitis C virus (HCV) remains a major health problem affecting approximately 58 million people worldwide. In the era of interferon (IFN)-based regimens, patients particularly infected with genotypes 1 and 4 achieved a low response rate. The implementation of direct-acting antivirals changed the landscape of HCV treatment. The increase in effectiveness provided us with the hope of eliminating HCV as a significant public threat by 2030. In the following years, there was an observed improvement in the treatment of HCV with genotype-specific regimens and highly effective pangenotypic options that are the most recent stage of the revolution. The optimization of therapy was accompanied by changes in the patient profile from the beginning of the IFN-free era over time. Patients treated with antiviral therapies were younger in successive periods, less burdened with comorbidities and comedications, more frequently treatment-naïve and had less advanced liver disease. Before the IFN-free era, specific subpopulations such as patients with HCV/HIV coinfection, those with a history of previous treatment, patients with renal impairment or with cirrhosis had lower chances for a virologic response. Currently, these populations should no longer be considered difficult to treat. Despite the high effectiveness of HCV therapy, there is a small percentage of patients with treatment failure. However, they can be effectively retreated with pangenotypic rescue regimens.     

Direct-acting antiviral regimens in Egyptian patients with chronic hepatitis C virus infection: A real-world single-center experience

Background and study aims:Chronic hepatitis C virus (HCV) infection has always been identified as a major health threat and a potential cause of liver cirrhosis, portal hypertension, and other associated problems. The introduction of direct-acting antiviral agents (DAAs) has represented a paradigm shift in HCV management. In this study, we aim to observe the rate of sustained virologic response (SVR12) in a large scale of patients at a single center as well as record the post-treatment changes in the hematologic, hepatic, and renal biochemical profiles.Patients and methodsIn total, 1933 chronic HCV genotype 4 mono-infected non-HCC patients who completed the treatment with six different DAA regimens in the Faculty of Medicine, Ain Shams University Research Institute (MASRI), were retrospectively enrolled in this study. The rate of sustained virologic response after 12 weeks off-therapy (SVR12) was assessed. The baseline characteristics to predict the SVR12 were then analyzed. The post-treatment changes in many profiles were recorded and analyzed.ResultsThe overall SVR12 rate was 96.2% (after excluding 84 cases who were lost to follow-up). It was achieved in 346/375 patients (92.3%), 466/477 patients (97.7%), 60/62 patients (96.8%), 11/11 patients (100%), 532/545 patients (97.6%), and 445/463 patients (96.1%) who received sofosbuvir/daclatasvir (SOF/DCV), sofosbuvir/daclatasvir/ribavirin (SOF/DCV/RBV), sofosbuvir/ledipasvir (SOF/LDV), sofosbuvir/ledipasvir/ribavirin (SOF/LDV/RBV), sofosbuvir/simeprevir (SOF/SMV), and ombitasvir/paritaprevir/ritonavir/ribavirin (OBV/PTV/r + RBV), respectively. In total, 73 patients (3.8%) failed to achieve SVR12. The baseline aspartate aminotransferase (AST), cirrhotic status, and treatment regimen were determined to have a significant impact on SVR12. In the overall treated population, the levels of serum AST, alanine aminotransferase, albumin, creatinine, bilirubin, and hemoglobin and platelet count improved significantly after treatment. Furthermore, sustained virologic response was strongly related to cirrhosis and its degree.ConclusionThe interferon-free DAA regimens offered high SVR12 rates in Egyptian patients with chronic HCV infection. They were associated with a significant improvement in the hematologic, hepatic, and renal biochemical profiles. The baseline AST, liver cirrhosis, and treatment regimen might have an impact on achieving SVR.     

Successful combination of direct antiviral agents in livertransplanted patients with recurrent hepatitis C virus

AIM To analyze the safety and efficiency of direct-actingantiviral(DAA) regimens in liver-transplanted patients with hepatitis C virus(HCV) reinfection.METHODS Between January 2014 and December 2016, 39 patients with HCV reinfection after liver transplantation were treated at our tertiary referral center with sofosbuvir(SOF)-based regimens, including various combinations with interferon(IFN), daclatasvir(DAC), simeprivir(SIM) and/or ledipasvir(LDV). Thirteen patients were treated with SOF + IFN ± RBV. Ten patients were treated with SOF + DAC ± RBV. Fiveteen patients were treated with fixed-dose combination of SOF + LDV ± RBV. One patient was treated with SOF + SIM + RBV. Three patients with relapse were retreated with SOF + LDV + RBV. The treatment duration was 12-24 wk in all cases. The decision about the HCV treatment was made by specialists at our transplant center, according to current available or recommended medications.RESULTS The majority of patients were IFN-experienced(29/39, 74.4%) and had a history of hepatocellular carcinoma(26/39, 66.7%) before liver transplantation. Sustained virological response at 12 wk(SVR12) was achieved in 10/13(76.9%) of patients treated with SOF + IFN ± RBV. All patients with relapse were treated with fixed-dose combination of SOF + LDV + RBV. Patients treated with SOF + DAC + RBV or SOF + LDV + RBV achieved 100% SVR12. SVR rates after combination treatment with inhibitors of the HCV nonstructural protein(NS)5 A and NS5 B for 24 wk were significantly higher, as compared to all other therapy regimens(P = 0.007). Liver function was stable or even improved in the majority of patients during treatment. All antiviral therapies were safe and well-tolerated, without need of discontinuation of treatment or dose adjustment of immunosuppression. No serious adverse events or any harm to the liver graft became overt. No patient experienced acute cellular rejection during the study period. CONCLUSION Our cohort of liver-transplanted patients achieved high rates of SVR12 after a 24-wk course of treatment, especially with combination of NS5 A and NS5 B inhibitors.     

老年CHC临床特点及抗病毒治疗策略研究进展

由于患者老龄化和病程不断延长,老年慢性丙型肝炎（chronic hepatitis C,CHC）患者的治疗越来越受到关注。由于老年患者感染丙型肝炎病毒（HCV）的时间较长,罹患肝硬化和肝癌的风险较高。老年丙型肝炎患者可能还伴有多种肝外基础疾病,如恶性肿瘤、肾脏疾病、糖尿病、心血管疾病和神经认知障碍等。目前,新型直接抗病毒药物（DAA）对老年CHC患者的抗病毒治疗效果和相关并发症情况尚不明了。有限的有关DAA治疗老年CHC患者的研究资料表明,年龄不应成为DAA治疗的障碍。     

Serum leptin and ghrelin in chronic hepatitis C patients with steatosis

AIM:To determine the associations between leptin and ghrelin concentrations and sustained virological response(SVR)in chronic hepatitis C patients with ste-atosis.METHODS:We retrospectively assessed 56 patients infected with hepatitis C virus(HCV)genotype-1 and 40 with HCV genotype-3.Patients with decompensated cirrhosis,and those with other causes of chronic liver disease,were excluded.Serum HCV-RNA concentra-tions were measured before the initiation of treatment;at weeks 12(for genotype 1 patients),24 and...     

Serum Mac-2 binding protein glycosylation isomer level predicts hepatocellular carcinoma development in E-negative chronic hepatitis B patients

BACKGROUND Liver cirrhosis is a major risk factor for hepatocellular carcinoma(HCC)development in chronic hepatitis B(CHB). Serum Mac-2 binding protein glycosylation isomer(M2 BPGi) is a novel serological marker for fibrosis. The role of M2 BPGi in prediction of HCC is unknown.AIM To examine the role of serum M2 BPGi in predicting HCC development in hepatitis B e antigen(HBeAg)-negative patients.METHODS Treatment-naive CHB patients with documented spontaneous HBeAg seroconversion were recruited. Serum M2 BPGi was measured at baseline(within3 years from HBeAg seroconversion), at 5 years and 10 years after HBeAg seroconversion and expressed as cut-off index(COI). Multivariate cox regression was performed to identify predictors for HCC development. ROC analysis was used to determine the cut-off value of M2 BPGi.RESULTS Among 207 patients(57% male, median age at HBeAg seroconversion 40 years old) with median follow-up of 13.1(11.8-15.5) years, the cumulative incidence of HCC at 15 years was 7%. Median M2 BPGi levels were significantly higher in patients with HCC compared to those without HCC(baseline: 1.39 COI vs 0.38 COI, P 0.001; 5-year: 1.45 COI vs 0.47 COI, P 0.001; 10-year: 1.20 COI vs 0.55 COI, P = 0.001). Multivariate analysis revealed age at HBeAg seroconversion[odds ratio(OR) = 1.196, 95% confidence interval(CI): 1.034-1.382, P = 0.016] and baseline M2 BPGi(OR = 4.666, 95%CI: 1.296-16.802, P = 0.018) were significant factors predictive of HCC. Using a cut-off value of 0.68 COI, baseline M2 BPGi yielded AUROC of 0.883 with 91.7% sensitivity and 80.8% specificity.CONCLUSION High serum M2 BPGi within 3 years after HBeAg seroconversion was a strong predictor for subsequent HCC development in treatment-naive HBeAg-negative CHB patients.     

Previous hepatitis E virus infection,cirrhosis and insulin resistance in patients with chronic hepatitis C

Background

Hepatitis E virus (HEV) infection in patients with pre-existing liver disease has shown high morbidity and lethality. The consequences of HEV superinfection in patients with chronic hepatitis C virus (HCV) infection are not fully understood. This study aimed to evaluate the association between the presence of anti-HEV antibodies, liver cirrhosis, and insulin resistance.

Real life efficacy and safety of direct-acting antiviral therapy for treatment of patients infected with hepatitis C virus genotypes 1, 2and 3 in northwest China

BACKGROUND Regimens involving direct-acting antiviral agents(DAAs) are recommended for the treatment of infection with hepatitis C virus(HCV) genotypes 1, 2 and 3. But real-world data is still not enough, especially in Asia.AIM To investigate the efficacy and safety of DAA-based regimens in a real-life setting in China.METHODS This study included 366 patients infected with HCV genotypes 1, 2 and 3, with or without cirrhosis, who were observed between May 2015 and December 2018.They were treated with ledipasvir and sofosbuvir(SOF)(genotype 1) with or without ribavirin(RBV), SOF and RBV(genotype 2), or SOF and daclatasvir(genotype 3), with or without RBV, for 12 or more wk. The participants' sustained virological responses(SVR) at post-treatment week 12(SVR12) was the primary endpoint. The occurrence of adverse events and drug-drug interactions were recorded.RESULTS In the 366 patients, genotype 1(59.0%) was the most common genotype, followed by genotypes 2(34.4%) and 3(6.6%). Liver cirrhosis was diagnosed in 154(42.1%)patients. Fifty(13.7%) patients were treatment-experienced. Intention-to-treat analysis revealed that SVR12 was 86.3%(316/366). For modified intention-totreat analysis, SVR12 was achieved in 96.6% of overall patients(316/327), 96.3%in patients with genotype 1, 97.5% in those with genotype 2, and 95.0% in those with genotype 3. Most of the treatment failures were due to lack of follow-up(3cases had non-responses, 1 had virological breakthrough, 11 relapsed and 36 did not participate in the follow-up). There was no significant difference in SVR between different genotypes and liver statuses(P 0.05). Patients with lower alanine aminotransferase levels at baseline who achieved an end of treatment response were more likely to achieve SVR12(P 0.05). High SVR was observed regardless of age, gender, liver status, alpha-fetoprotein, HCV RNA levels or history of antiviral therapy(P 0.05 for all). The cumulative hepatocellular carcinoma occurrence and recurrence rate after using the DAAs was 0.9%. Most of the adverse events were mild. We found two cases of special adverse events.One case involved facial and bilateral lower extremity edema, and the other case showed an interesting change in lipid levels while on medication. No severe adverse events were noted.CONCLUSION The DAA-based regimens tested in this study have excellent effectiveness and safety in all patients infected with HCV genotypes 1, 2 and 3, including those with cirrhosis.