干扰素联合利巴韦林治疗慢性丙型肝炎的疗效观察

目的 探讨干扰素联合利巴韦林治疗慢性丙型肝炎(chronic hepatitis C,CHC)的临床疗效及对肝功能和肝纤维化指标的影响.方法 将滨州市人民医院2011年3月～2012年3月收治的88例CHC患者按照随机数字表法分为2组,每组44例.对照组单用干扰素治疗,观察组采用干扰素联合利巴韦林治疗,比较治疗后2组临床疗效和治疗前后2组肝功能和肝纤维化指标变化情况.结果 观察组治疗总有效率为90.91％,明显高于对照组的68.18％,2组比较差异具有统计学意义(P＜0.05);观察组治疗后ALT和AST分别为(70.24±7.94) U/L和(79.45±9.72) U/L,HA、PCⅢ、CⅣ和LN分别为(76.87±10.32) μg/L、(79.45±9.72) μg/L、(79.76±8.00) μg/L和(118.41±16.97) μg/L,均明显高于治疗前和对照组,差异具有统计学意义(P＜0.05).结论 干扰素联合利巴韦林治疗慢性丙型肝炎疗效显著,可明显改善患者肝功能,具有较好的抗纤维化作用.     

Treatment of chronic hepatitis C in elderly patients

Importance of the field: The issue of age in cases of chronic hepatitis C (HCV) in the West is a major problem; the average age of patients with HCV is increasing and its prevalence increases with advancing age.

Areas covered in this review: This review is devoted to the analysis of the limited number of clinical studies performed to treat HCV in elderly patients.

What the reader will gain: The importance of the age factor is outlined in nearly all the studies done in the field. Advanced age is associated with a lower sustained virologic response (SVR) rate. Moreover, in elderly patients, these studies also tend to suggest that, before initiating an antiviral treatment, the physician should not only take into account the classical parameters associated with SVR but also the presence of co-morbidities and life expectancy.

Take-home messages: Antiviral therapy should be used in selected elderly HCV patients with advanced fibrosis and more studies are required in this population to better define the parameters associated with SVR. As age is an important factor in the success of antiviral therapy, starting antiviral treatment at a young age should be favored.     

PR 治疗慢性丙型肝炎患者营养风险的影响因素分析

摘要： 目的 探讨使用聚乙二醇干扰素联合利巴韦林 （PR） 治疗的慢性丙型肝炎 （丙肝） 患者出现营养风险的影响因素。方法 选取接受 PR 治疗的慢性丙肝患者 175 例, 测量身高、 体质量, 计算体质指数 （BMI）, 用营养风险筛查 2002 （NRS 2002） 来进行营养风险评估, 并分为有风险组 （140 例） 和无风险组 （35 例）。结果 2 组间年龄、 HCV 基因型、 临床类型、 治疗时间及干扰素或利巴韦林是否减量差异有统计学意义 （P＜0.05）。Logistic 回归分析显示： 高龄（OR 值 16.068, β 值 2.777）、 干扰素减量 （OR 值 3.096, β 值 1.130）、 利巴韦林减量 （OR 值 3.382, β 值 1.219） 以及进展至肝硬化的慢性丙肝 （OR 值 5.092, β 值 1.628） 为营养风险的危险因素; 而 HCV 基因型为非 1b 型者 （OR 值 0.384, β 值-0.957） 为营养风险的保护因素。结论 接受 PR 治疗的慢性丙肝患者营养风险发生率高。高龄、 对 PR 不耐受、慢性丙肝进展为肝硬化的患者为发生营养风险的独立危险因素, 而非 1b型 HCV 感染者不易发生营养风险。     

TMC435 for the treatment of chronic hepatitis C

Introduction: Chronic hepatitis C (CHC) virus infection affects more than 170 million people globally. The aim of treatment of CHC is to effect sustained elimination of the virus (a sustained virological response, SVR). Prior to the development of direct-acting antiviral (DAA) agents, the standard of care (SOC) for CHC comprised combined treatment with pegylated interferon (PegIFN) and ribavirin (RBV).

Areas covered: TMC435 (Tibotec pharmaceuticals) is a macrocyclic non-covalent NS3/NS4A protease inhibitor (DAA) that is currently in Phase III clinical development. TMC435 is being developed in treatment regimens both with and without PegIFN and RBV. In Phase IIb clinical trials, the addition of TMC435 to current SOC significantly increased the SVR rate in both treatment-naive and experienced patients with CHC. It differs, however, from the other first-generation protease inhibitors in that it is administered once daily, has a different tolerability and resistance profile and has activity against CHC genotypes 1 – 6 with the exception of genotype 3. Furthermore, the addition of TMC435 to PegIFN/RBV appears to be able to significantly shorten treatment duration in the majority of patients. This article will review the pharmacology, pharmacodynamics, safety and efficacy of TMC435 by evaluating the preclinical and clinical studies to date.

Expert opinion: TMC435 is a ‘second-wave' protease inhibitor that has the potential to play a pivotal role in the next phase of CHC treatment. The forthcoming results of Phase III trials involving TMC435 are awaited with interest.     

聚乙二醇干扰素治疗丙型肝炎的新进展

慢性丙型肝炎是一种严重威胁人类健康的疾病。聚乙二醇干扰素作为一种最近进入临床应用的药物 ,由于其独特的药动学特点在治疗慢性丙型肝炎的临床试验中显示出比普通干扰素更好的疗效。而聚乙二醇干扰素联合利巴韦林治疗目前被证明是治疗慢性丙型肝炎的最佳疗法。在临床试验中发现聚乙二醇干扰素的耐受性要优于普通干扰素     

聚乙二醇干扰素α-2a联合利巴韦林治疗不同年龄慢性丙型肝炎患者的临床效果

目的 探讨聚乙二醇干扰素α-2a联合利巴韦林治疗不同年龄慢性丙型肝炎患者的临床效果.方法 回顾性分析2010年1月～2014年1月本院收治的慢性丙型肝炎患者83例,根据年龄的不同将其分为＜60岁组（n=43）和≥60岁组（n=40）.两组患者均给予聚乙二醇干扰素α-2a联合利巴韦林治疗,观察比较两组的治疗效果及不良反应发生情况.结果 治疗48周后,＜60岁组患者的快速病毒学应答（RVR）率（65.1％）、早期病毒学应答（EVR）率（72.1％）、治疗结束时病毒学应答（ETVR）率（69.8％）、持续病毒学应答（SVR）率（51.2％）均高于≥60岁组（分别为50.0％、57.5％、87.5％、40.0％）,差异有统计学意义（P＜0.05或P＜0.01）;两组复发率、无效率比较,差异无统计学意义（P＞0.05）.＜60岁组患者中性粒细胞、血小板、血红蛋白下降率明显低于≥60岁组,差异有统计学意义（P＜0.05或P＜0.01）;两组患者主要不良反应为恶心、呕吐、乏力、脱发不适症状,且＜60岁组恶心、呕吐、乏力的发生率低于≥60岁组,差异有统计学意义（P＜0.05）.结论 老年慢性丙型肝炎患者抗病毒疗效较差,药物不良反应发生率较高,治疗上仍存在一定的难度,针对老年患者制订安全有效的抗病毒治疗方案,对于降低肝硬化、肝癌的发生率至关重要.     

最新丙型病毒性肝炎诊治指南推荐方案

本文重点围绕2011年欧洲肝病研究学会(EASL)发布的HCV感染的诊疗指南(EASL 2011),以及美国肝病研究学会(AASLD)发布的针对基因1型慢性丙型肝炎病毒感染治疗指南(AASLD 2011),对急、慢性丙型肝炎、难治性丙型肝炎及合并其他并发症的丙型肝炎推荐治疗意见,针对基因1型HCV感染的聚乙二醇化干扰素、利巴韦林和蛋白酶抑制剂三联治疗方案等进行综合分析,以期指导国内临床丙型肝炎的诊治。     

Safety of direct-acting antivirals in the treatment of chronic hepatitis C

Introduction: Combination therapy with pegylated interferon, ribavirin and the two first-generation NS3/4A protease inhibitors (PIs), telaprevir (TVR) and boceprevir (BOC), is the new standard-of-care therapy for patients who are chronically infected with genotype 1 hepatitis C virus. These combinations significantly increase sustained virological response (SVR) rates, but they also increase the rates of adverse events (AEs). Appearance of significant AEs may necessitate dose reduction or discontinuation of treatment, and may impact on virological response.

Areas covered: In registration trials, IFN-related AEs were a dominant feature in both types of therapy. Some events were more frequent with PI-containing regimens, like anemia and dysgeusia with BOC and anemia, pruritus, rash and anorectal symptoms with TVR. This review addresses the early identification and management of AEs to improve tolerance, and to avoid reduction in SVR rates.

Expert opinion: Every patient will experience adverse effects to differing degrees; a systematic approach to their management can be very helpful. Early recognition and intervention can help clinicians ensure that patients are able to complete therapy where possible and achieve the goal of viral eradication. Treatment with the next generation of antivirals will improve safety and efficacy.     

Pharmacokinetics of ribavirin in combined interferon-alpha 2b and ribavirin therapy for chronic hepatitis C virus infection

AIMS: The aim of this study was to clarify the pharmacokinetics of ribavirin and interferon-alpha (IFN-alpha) 2b when administered in combination for 24 weeks and effects of pharmacokinetics of both on treatment outcome in chronic hepatitis C with genotype 1b and high viral load. METHODS: In this multicentre open study, 27 patients received 2-week daily induction therapy followed by 22-week, three-times-a-week maintenance therapy of intramuscular IFN-alpha 2b at a dose of 6 million units and oral ribavirin at 400 mg twice daily for 24 weeks, and followed up for 24 weeks post-treatment. Single- and multiple-dose pharmacokinetic studies were assessed by serial measurements of serum concentrations of both compounds at weeks 1 and 24. RESULTS: Five patients attained sustained virological response. Serum ribavirin concentrations asymptoted after 4-8 weeks of treatment in all patients. The steady-state concentration correlated significantly with serum ribavirin clearance after multiple dosing (r = -0.875; 95% CI -0.932, -0.721; P < 0.001). Serum concentrations at weeks 4 and 8, Cmax and AUC(0,12 h) after multiple dosing and AUC(0,28 weeks) of ribavirin were significantly higher in sustained virological responders than in virological responders or nonresponders (P < 0.05, each). Increased Cmax and accumulation index of AUC(0,12 h) (median 10.5; 95% CI 6.4, 12.4), and prolonged washout half-life after multiple dosing reflected accumulation and slow clearance of ribavirin from the tissue compartments. CONCLUSIONS: Continuous exposure and accumulation of ribavirin may be necessary for sustained virological response to combination therapy in chronic hepatitis C with genotype 1b and high viral load.     

Successful treatment of chronic hepatitis C with pegylated interferon in combination with ribavirin in a methadone maintenance treatment program

Injection drug users constitute 60% of the more than 4 million people in the United States with hepatitis C virus (HCV), including many methadone maintenance patients. Few data exist describing clinical outcomes for patients receiving HCV treatment on-site in methadone maintenance settings. In this retrospective study, we describe clinical outcomes for 73 patients receiving HCV treatment on-site in a methadone maintenance treatment program. Fifty-five percent of patients achieved end-of-treatment response, and 45% achieved sustained viral response. These treatment response rates are nearly equivalent to previously published HCV treatment response rates, despite high prevalences of ongoing drug use (49%), psychiatric comorbidity (67%), and HIV coinfection (32%). These data show that on-site HCV treatment with pegylated interferon and ribavirin is effective in methadone-maintained patients, many of whom are active drug users, psychiatrically ill, or HIV coinfected, and that methadone maintenance treatment programs represent an opportunity to safely treat chronic hepatitis C.     

Developments in the treatment of chronic hepatitis C

Hepatitis C virus is the most common chronic, blood-bourne infection, affecting 170 million people worldwide, approximately 3% of the global population. Of those infected with hepatitis C virus, 50 – 85% will develop chronic hepatitis C. Although hepatitis C is primarily a disease of the liver, a diagnosis is currently defined by the presence of the hepatitis C virus and treatment success is defined by the clearance of the virus. IFN-α is currently the mainstay of chronic hepatitis C therapy; the antiviral and anti-inflammatory components of IFN target both the infectious and the hepatic manifestations of the disease. However, even in combination with ribavirin, interferon therapy is not fully efficacious. Recently, the search for a more effective treatment has led investigators to optimise interferon therapy by developing pegylated interferons. Challenges facing our current treatment of hepatitis C virus include lack of efficacy in patients with difficult-to-treat disease, such as patients with cirrhosis or infected with hepatitis C virus genotype 1 (who represent a majority of US hepatitis C virus infections), the toxicity of combination therapy, the expense and difficulty of therapy and the poor reception of these treatments by many patients. The development of new hepatitis C antiviral agents is critical to our management of this disease. A number of approaches are under investigation, including long-acting interferons, immunomodulators, antifibrotics, specific hepatitis C virus-derived enzyme inhibitors, drugs that either block hepatitis C virus antigen production from RNA or prevent normal processing of hepatitis C virus proteins and other molecular approaches to treating hepatitis C virus, such as ribozymes and antisense oligonucleotides.     

Pegylated interferon alpha 2a for the treatment of hepatitis C virus infection

Introduction: Treatments for hepatitis C virus (HCV) infection have advanced rapidly in the last decade. Pegylated interferon alpha 2a (PEG-IFN alpha 2a) alone, in combination with ribavirin and with or without direct acting antivirals (DAAs) is modestly effective in the treatment of chronic HCV infection.

Areas covered: The review describes the chemistry, pharmacokinetic and pharmacodynamic properties, clinical efficacy, safety and drug-drug interaction profiles of PEG-IFN alpha 2a.

Expert opinion: Despite the availability of DAAs and its formidable toxicity profile, PEG-IFN alpha 2a retains a role for the treatment of acute HCV and chronic HCV infection in resource limited settings and for end-stage renal disease patients and others who cannot access DAAs or are DAA-ineligible. Knowledge of pharmacogenetic profiles which favor successful treatment outcomes with IFN-based therapies may allow for selection of best candidates for the regimen.     

Patient characteristics associated with peglyated interferon alfa‐2a induced neutropenia in chronic hepatitis C patients

Neutropenia is a haematologic disorder commonly reported in patients with chronic hepatitis C virus (HCV) infection treated with pegylated interferon alfa‐2a (PEG‐IFN α‐2a). The objective of the present project is to identify patient characteristics associated with neutropenia in hepatitis C patients. Demographic, clinical, and genetic data from 715 patients with chronic HCV infection treated with PEG‐IFN α‐2a and ribavirin. The outcome variable was the development of grade 3 or 4 neutropenia, defined as the decrease in neutrophil counts below 1 10⁹/L anytime during study. Predictors of neutropenia were identified using a 2‐stage approach. First, univariate analysis was performed to identify possible predictors of neutropenia. T test was used for continuous variables and Fisher's exact test was used for categorical variables. Second, multiple logistic regression with stepwise addition was then performed using predictors identified in the univariate analysis step to produce final model containing independent predictors at P < .05. Logistic regression identified female gender, absolute neutrophils counts, and cholesterol level as the main predictors of neutropenia. Female gender increases the odds of experiencing neutropenia by 86% compared to male gender. A 1 unit (mmol/L) increase in cholesterol level decreases the odds of developing neutropenia by 13%. A 55% reduction in the likelihood of developing neutropenia for a 1 unit (10⁹/L) increase in the absolute neutrophils counts. Patients with high risk of developing neutropenia can be identified. Identification of this cohort allows early intervention to prevent neutropenia. Possible intervention is to administer drugs that raise neutrophil count such as filgrastim before neutropenia occurs.     

α—2b干扰素治疗慢性丙型肝炎的经济学评价

目的：对上海、北京和三石家庄三城市应用α－２ｂ干扰素治疗慢性丙型肝炎做经济学评价。方法：根据对三城市的部分慢性丙肝、代偿性肝硬化、失代偿性肝硬化病人调查所得的门诊费用、住院费用,并根据慢性丙型肝炎的自然史和α－２ｂ干扰素治疗组和常规治疗组的慢性丙肝病人在３０ａ内的有关费用和预后,并进行成本－效益和成本－效果分析。结果：治疗后３０ａ内,α－２ｂ干扰素治疗组比常规治疗组增加８５２个存活人年和１４８７个     

Retreatment of chronic hepatitis C in previous non-responders and relapsers

Therapy for chronic hepatitis C has improved dramatically over the past 20 years. Unfortunately, ～ 50% of those treated do not have a durable response to therapy. Non-responders and relapsers after previous interferon-based therapy are particularly challenging with regard to clinical management. This article provides a general overview of the treatment of hepatitis C and reviews present data regarding management of patients with chronic hepatitis C who are non-responders or relapsers after previous treatment. The review ends with the authors' opinion regarding present management of non-responders and relapsers and future emerging therapies.     

长效干扰素联合利巴韦林治疗慢性丙肝临床观察

目的 观察长效干扰素聚乙二醇干扰素(PEG-IFN)α-2a与普通干扰素(IFN)α-1b治疗慢性丙型肝炎(CHC)的临床疗效及安全性.方法 60例CHC患者分别采用PEG-IFNα-2a和IFNα-1b联合应用利巴韦林治疗,疗程48周,24周后随访.观察两组在病毒学应答和生化学应答以及药物不良反应方面的差异.结果 长...     

Taribavirin for the treatment of chronic hepatitis C

Background: The current standard therapy for chronic hepatitis C virus (HCV), combination therapy with pegylated interferon and ribavirin, is plagued by a number of side effects, most notably anemia. This anemia is typically managed with a reduction of ribavirin dosing, which may lead to reduced efficacy. Taribavirin, an oral prodrug of ribavirin, which has been shown to induce a lesser degree of anemia, is being investigated for the treatment of chronic HCV. Objective: To summarize the clinical trials involving taribavirin and its potential role in the treatment of chronic HCV. Methods: Information was obtained via searches for data related to taribavirin, as well as other current and investigational therapies for chronic HCV. Press releases discussing otherwise unpublished trial outcomes were obtained from the website of Valeant Pharmaceuticals, the producer of Viramidine^® (taribavirin). Conclusion: Taribavirin may increase adherence to therapy for chronic HCV by reducing the need for dose reduction due to anemia. A recent Phase II trial investigating early and sustained virological response showed no statistically significant differences between ribavirin 1000/1200 mg and taribavirin at 800-, 1200-, or 1600-mg dosing, while illustrating a lesser degree of anemia in 800- and 1200-mg dosing of taribavirin. Ongoing studies will continue to examine the efficacy of combination therapy with taribavirin in the place of ribavirin.     

Pharmacodynamic and pharmacokinetic evaluation of the combination of daclatasvir/sofosbuvir/ribavirin in the treatment of chronic hepatitis C

Introduction: The combination of daclatasvir (DCV), sofosbuvir (SOF), and ribavirin (RBV) is a direct-acting antiviral (DAA) regimen for the treatment of hepatitis C virus (HCV) infection. The inclusion of newer effective DAAs such as SOF and DCV with high efficacy and excellent tolerance introduced a new scenario in HCV infection therapy: high rates of sustained virological response (SVR), shorter therapies, less toxicity, and interferon-free treatments. This combination was approved for the treatment of HCV in treatment-naive or treatment-experienced patients with chronic HCV genotype 1 or 3 infection.

Areas covered: This review summarizes the pharmacokinetics, pharmacodynamics, efficacy, and safety of DCV plus SOF and RBV therapy in the treatment of HCV infection. The topics include data regarding drug absorption, distribution, metabolism, excretion, and antiviral activity strategies, such as clinical dose selection and treatment duration.

Expert opinion: This combination, taken orally with or without food, has an excellent pharmacokinetic and pharmacodynamic profile. DAC/SOF/RBV achieves very high rates of SVR in treatment-naive and treatment-experienced patients with chronic HCV infection, including difficult-to-treat patients such as those with compensated cirrhosis, post-transplant recurrence, or HIV-1 co-infection.