Aplastic anemia and severe pancytopenia during treatment with peg-interferon,ribavirin and telaprevir for chronic hepatitis C

Telaprevir and Boceprevir are the first direct acting antivirals approved for chronic hepatitis C in combination with peg-interferon alfa and ribavirin.Pancytopenia due to myelotoxicity caused by these drugs may occur,but severe hematological abnormalities or aplastic anemia(AA) have not been described.We collected all cases of severe pancytopenia observed during triple therapy with telaprevir in four Spanish centers since approval of the drug in 2011.Among 142 cirrhotic patients receiving treatment,7 cases of severe pancytopenia(5%) were identified and three were consistent with the diagnosis of AA.Mean age was 59 years,five patients had compensated cirrhosis and two patients had severe hepatitis C recurrence after liver transplantation.Severe pancytopenia was diagnosed a median of 10 wk after the initiation of therapy.Three patients had pre-treatment hematological abnormalities related to splenomegaly.In six patients,antiviral treatment was interrupted at the onset of hematological abnormalities.Two patients died due to septic complications and one patient due to acute alveolar hemorrhage.The remaining patients recovered.Severe pancytopenia and especially AA,are not rare during triple therapy with telaprevir in patients with advanced liver disease.Close monitoring is imperative in this setting to promptly detect serious hematological disorders and to prevent further complications.

Telaprevir/boceprevir era: From bench to bed and back

Hepatitis C virus (HCV) infects approximately 200 million people worldwide. Interferon-based therapies have dominated over the past two decades. However, the overall response rates remain suboptimal. Thanks to the tremendous effort from both academia and industry, two serine protease inhibitors telaprevir and boceprevir for treating chronic hepatitis C have finally reached the clinic. Although these compounds are only approved for combination use with interferon and ribavirin in genotype 1 HCV infected chronic patients, the management of HCV patients however is now evolving incredibly. Here, we overviewed a series of landmark studies, regarding the clinical development of telaprevir and boceprevir. We discussed the mechanism-of-action of telaprevir/boceprevir and their potential application in HCV-positive liver transplantation patients. We further emphasized some emerging concerns with perspective of further development in this field.

Coadministration of telaprevir and transcatheter arterial chemoembolization in hepatitis C virus-associated hepatocellular carcinoma

The use of directacting antiviral agents (e.g. , telaprevir, boceprevir) has improved response rates in patients with hepatitis C virus (HCV) genotype 1 infections. Substantial number of drug-drug interactions are anticipated with the use of telaprevir, a cytochrome P450 3A and P-glycoprotein substrate and inhibitor. Herein we describe a patient with HCV-associated hepatocellular carcinoma treated simultaneously with a telaprevir-containing regimen and localized chemo-therapy (transcatheter arterial chemoembolization) with doxorubicin. No clinically relevant interactions or adverse events developed while on antiviral therapy.

Comparison of peg-interferon, ribavirin plus telaprevir vs simeprevir by propensity score matching

AIM: To compare efficacy of telaprevir(TVR) and simeprevir(SMV) combined with pegylated interferon(PEG-IFN) and ribavirin(RBV) while treating chronic hepatitis C(CHC). METHODS: In all, 306 CHC patients were included in this study. There were 159 patients in the TVR combination therapy group and 147 patients in the SMV combination therapy group. To evaluate pretreatment factors contributing to sustained virological response at 12 wk(SVR12), univariate and multivariate analyses were performed in TVR and SMV groups. To adjust for patient background between TVR and SMV groups, propensity score matching was performed. Virological response during treatment and SVR12 were evaluated.RESULTS: Overall rates of SVR12 [undetectable serum hepatitis C virus(HCV) RNA levels] were 79.2% and 69.4% in TVR and SMV groups, respectively. Patients in the SMV group were older, had higher serum HCV RNA levels, lower hemoglobin, higher prevalence of unfavorable interleukin-28B(IL28B) genotype(rs8099917), and poorer response to previous PEG-IFN and RBV treatment. Propensity score matching was performed to adjust for backgrounds(n = 104) and demonstrated SVR12 rates of 74.0% and 73.1% in the TVR and SMV groups, respectively. In the TVR group, discontinuation rates were higher because of adverse events; however, breakthrough and nonresponse was more frequent in the in SMV group. Multivariate analysis revealed IL28 B genotype(rs8099917) as the only independent predictive factor of SVR12 in both groups.CONCLUSION: SVR12 rates were almost identical following propensity score matching.

Boceprevir or telaprevir in hepatitis C virus chronic infection:The Italian real life experience

AIM: To check the safety and efficacy of boceprevir/telaprevir with peginterferon/ribavirin for hepatitis C virus(HCV) genotype 1 in the real-world settings. METHODS: This study was a non-randomized, observational, prospective, multicenter. This study involved 47 centers in Italy. A database was prepared for the homogenous collection of the data, was used by all of the centers for data collection, and was updated continuously. All of the patients enrolled in this study were older than 18 years of age and were diagnosed with chronic infection due to HCV genotype 1. The HCV RNA testing was performed using COBAS-Taq Man2.0(Roche, LLQ 25 IU/m L). RESULTS: All consecutively treated patients were included. Forty-seven centers enrolled 834 patients as follows: Male 64%; median age 57(range 18-78), of whom 18.3% were over 65; mean body mass index 25.6(range 16-39); genotype 1b(79.4%); diagnosis of cirrhosis(38.2%); and fibrosis F3/4(71.2%). The following drugs were used: Telaprevir(66.2%) and PEG-IFN-alpha2a(67.6%). Patients were na?ve(24.4%), relapsers(30.5%), partial responders(14.8%) and null responders(30.3%). Overall, adverse events(AEs) occurred in 617 patients(73.9%) during the treatment. Anemia was the most frequent AE(52.9% of cases), especially in cirrhotic. The therapy was stopped for 14.6% of the patients because of adverse events or virological failure(15%). Sustained virological response was achieved in 62.7% of the cases, but was 43.8% in cirrhotic patients over 65 years of age. CONCLUSION: In everyday practice, triple therapy is safe but has moderate efficacy, especially for patients over 65 years of age, with advanced fibrosis, nonresponders to peginterferon + ribavirin.

Telaprevir- and boceprevir-based tritherapies in real practice for F3-F4 pretreated hepatitis C virus patients

AIM:To assess,in a routine practice setting,the sus-tained virologic response(SVR) to telaprevir(TPV) or boceprevir(BOC) in hepatitis C virus(HCV) nullresponders or relapsers with severe liver fibrosis.METHODS:One hundred twenty-five patients were treated prospectively for 48 wk with TPV or BOC + pegylated-interferon(peg-INF) α2a + ribavirin(PR) according to standard treatment schedules without randomization.These patients were treated in routine practice settings in 10 public or private health care centers,and the data were prospectively collected.Only patients with severe liver fibrosis(Metavir scores of F3 or F4 upon liver biopsy or liver stiffness assessed by elastography),genotype 1 HCV and who were null-responders or relapsers to prior PR combination therapy were included in this study.RESULTS:The Metavir fibrosis scores were F3 in 35(28%) and F4 in 90(72%) of the patients.In total,62.9% of the patients were null-responders and 37.1% relapsers to the previous PR therapy.The overall SVR rate at 24 wk post-treatment withdrawal was 59.8%.The SVR was 65.9% in the TPV group and 44.1% in the BOC group.Independent predictive factors of an SVR included a response to previous treatment,relapsers vs null-responders [OR = 3.9;(1.4,10.6),P = 0.0084],a rapid virological response(RVR) [OR 6.9(2.6,18.2),P = 0.001] and liver stiffness lower than 21.3 kPa [OR = 8.2(2.3,29.5),P = 0.001].During treatment,63 patients(50.8%) had at least one severe adverse event(SAE) of grade 3 or 4.A multivariate analysis identified two factors associated with SAEs:female gender [OR = 2.4(1.1,5.6),P = 0.037] and a platelet count below 150 × 103/ mm3 [OR = 5.3(2.3,12.4),P ≤ 0.001].CONCLUSION:More than half of these difficult-to-treat patients achieved an SVR and had SAEs in an actual practice setting.The SVR rate was influenced by the response to previous PR treatment,the RVR and liver stiffness.

Efficacy and safety of telaprevir- and simeprevir-based triple therapies for older patients with chronic hepatitis C

AIMTo evaluate and compare the efficacy and safety of telaprevir (TVR)-and simeprevir (SMV)-based triple therapies in elderly patients, specifically patients aged 66 years or older. METHODSThe present study enrolled 112 and 76 Japanese patients with chronic hepatitis C virus genotype 1b infection who were treated with a 12-wk TVR-based or SMV-based triple therapy, respectively, followed by a dual therapy that included pegylated interferon α and ribavirin (RBV) for 12 wk. The patients were categorized into two groups according to age as follows: A younger group of patients aged ≤ 65 years old and an older group of patients aged > 65 years old. Among the patients treated with TVR-based triple therapy, 34 patients were included in the older group. The median ages were 56 years (range: 28-65 years) in the younger group and 69 years (range: 66-81 years) in the older group. Among the patients treated with SMV-based triple therapy, 39 patients were included in the older group. The median ages were 59 years (range: 36-65 years) in the younger group and 71 years (range: 66-86 years) in the older group. The clinical, biochemical and virological data were analyzed before and during treatment. RESULTSAmong the patients treated with the TVR-based triple therapy, no significant difference in the sustained virological response (SVR) was found between the younger (80.8%) and older (88.2%) groups. The SVR rates for patients with the interleukin 28B (IL28B) (rs8099917) TG/GG-genotypes (73.9% and 60.0% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (86.3% and 92.9%, respectively). The cumulative exposure to RBV for the entire 24-wk treatment period (as a percentage of the target dose) was significantly higher in the younger group than in the older group (91.7% vs 66.7%, respectively, P vs 81.9%, respectively). A multivariate analysis identified the TT-genotype of IL28B (OR = 8.160; 95%CI: 1.593-41.804, P = 0.012) and the adherence of RBV (> 60%) (OR = 11.052; 95%CI: 1.160-105.273, P = 0.037) as independent factors associated with the SVR. Adverse events resulted in discontinuation of the treatment in 11.3% and 14.7% of the younger and older groups, respectively. Among the patients treated with the SMV-based triple therapy, no significant difference in the SVR rare was found between the younger (81.1%) and older (82.1%) groups. The SVR rates for patients with the IL28B TG/GG-genotypes (77.8% and 64.7% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (88.2% and 100%, respectively). A multivariate analysis identified the TT-genotype of IL28B as an independent factor associated with the SVR (OR = 9.677; 95%CI: 1.114-84.087, P = 0.040). Adverse events resulted in discontinuation of the treatment in 7.0% and 14.3% of patients in the younger and older groups, respectively. CONCLUSIONBoth TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with genotype 1b chronic hepatitis C. Genotyping of the IL28B indicates a potential to achieve SVR in these difficult-to-treat elderly patients.

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 GT1 a 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.

Factors associated with success of telaprevir-and boceprevir-based triple therapy for hepatitis C virus infection

To evaluate new therapies for hepatitis C virus (HCV), data about real-world outcomes are needed. METHODSOutcomes of 223 patients with genotype 1 HCV who started telaprevir- or boceprevir-based triple therapy (May 2011-March 2012) at the Mount Sinai Medical Center were analyzed. Human immunodeficiency virus-positive patients and patients who received a liver transplant were excluded. Factors associated with sustained virological response (SVR24) and relapse were analyzed by univariable and multivariable logistic regression as well as classification and regression trees. Fast virological response (FVR) was defined as undetectable HCV RNA at week-4 (telaprevir) or week-8 (boceprevir). RESULTSThe median age was 57 years, 18% were black, 44% had advanced fibrosis/cirrhosis (FIB-4 ≥ 3.25). Only 42% (94/223) of patients achieved SVR24 on an intention-to-treat basis. In a model that included platelets, SVR24 was associated with white race [odds ratio (OR) = 5.92, 95% confidence interval (CI): 2.34-14.96], HCV sub-genotype 1b (OR = 2.81, 95%CI: 1.45-5.44), platelet count (OR = 1.10, per x 104 cells/μL, 95%CI: 1.05-1.16), and IL28B CC genotype (OR = 3.54, 95%CI: 1.19-10.53). Platelet counts > 135 x 103/μL were the strongest predictor of SVR by classification and regression tree. Relapse occurred in 25% (27/104) of patients with an end-of-treatment response and was associated with non-FVR (OR = 4.77, 95%CI: 1.68-13.56), HCV sub-genotype 1a (OR = 5.20; 95%CI: 1.40-18.97), and FIB-4 ≥ 3.25 (OR = 2.77; 95%CI: 1.07-7.22). CONCLUSIONThe SVR rate was 42% with telaprevir- or boceprevir-based triple therapy in real-world practice. Low platelets and advanced fibrosis were associated with treatment failure and relapse.

NS3/4A丝氨酸蛋白酶抑制剂——Telaprevir

Telaprevir是美国Vertex制药公司开发的一种丙型肝炎病毒(HCV)NS3/4A丝氨酸蛋白酶抑制剂,能抑制HCV的病毒复制。在欧洲和美国开展的国际多中心、双盲、对照III期临床试验结果显示,本品具有提高HCV感染患者持续病毒学应答(sustained viral response,SVR)的作用,确定了其治疗HCV感染的有效性及耐受性。2011年5月23日,美国FDA批准本品与聚乙二醇干扰素α和利巴韦林联用,用于治疗成人慢性丙型肝炎,商品名"Incivek"。

Telaprevir合聚乙二醇干扰素α及利巴韦林治疗慢性丙型肝炎疗效的荟萃分析

目的了解Telaprevir联合聚乙二醇干扰素（Peg-IFN）α、利巴韦林对基因I型HCV感染慢性丙型肝炎患者的疗效及安全性。方法采用Meta分析方法对国外2009-2011年发表的Telaprevir、Peg-IFNα及利巴韦林三联疗法治疗慢性丙型肝炎的相关研究结果进行合并效应值和异质性相关因素分析。共收集相关文献6篇，累计病例2677例。其中，Telaprevir、Peg—IFNα利巴韦林治疗组（TPR组）1850例，干扰素仅、利巴韦林治疗组（PR组）827例。用Meta分析方法合并OR值或RR值及其95％可信区间。采用基于X2检验的Q检验法分析各研究的组间异质性。通过去除任意一个研究进行敏感性分析，以进一步证实研究结果的可信性。结果1850例TPR组患者中，获得快速病毒学应答（RVR）者1041例，占56．3％；获得持续病毒学应答（SVR）者1235例，占66．8％；复发率为12．1％（176／1460）。827例PR组患者中，获得RVR者58例，占7．0％；获得SVR者296例，占35．8％；复发率为32．3％（145／449）。TPR组RVR、SVR均明显高于PR组（合并OR值分别为29．83和3．97，95％CI分别为16．16～55．05和2．58～6．11，P值均〈0．01），复发率明显低于PR组（合并RR值为0．36，95％CI0．24～0．56，P〈0．01）。结论Telaprevir联合Peg—IFNα、利巴韦林治疗对HCV基因I型的慢性丙型肝炎患者的疗效显著，但要注意防治不良反应。

丙型肝炎病毒直接抗病毒药物的研究进展

全球丙型肝炎病毒（Hepatitis C Virus，HCV）感染者超过1．8亿，HCV感染可导致慢性肝病、肝硬化和肝细胞癌（HCC）等疾病，已成为严重的健康问题。HCV是基因组大小9．6kb的单链RNA病毒，属黄病毒科，丙型肝炎病毒属，

Chronic hepatitis C:This and the new era of treatment

Over the last years it has started a real revolution in the treatment of chronic hepatitis C. This occurred for the availability of direct-acting antiviral agents that allow to reach sustained virologic response in approximately 90% of cases. In the near future further progress will be achieved with the use of pan-genotypic drugs with high efficacy but without side effects.

Evidence-based consensus on the diagnosis, prevention and management of hepatitis C virus disease

Hepatitis C virus(HCV) is a potent human pathogen and is one of the main causes of chronic hepatitis round the world. The present review describes the evidencebased consensus on the diagnosis, prevention and management of HCV disease. Various techniques, for the detection of anti-HCV immunoglobulin G immunoassays, detection of HCV RNA by identifying virus-specific molecules nucleic acid testings, recognition of core antigen for diagnosis of HCV, quantitative antigenassay, have been used to detect HCV RNA and core antigen. Advanced technologies such as nanoparticlebased diagnostic assays, loop-mediated isothermal amplification and aptamers and Ortho trak-C assay have also come to the front that provides best detection results with greater ease and specificity for detection of HCV. It is of immense importance to prevent this infection especially among the sexual partners, injecting drug users, mother-to-infant transmission of HCV, household contact, healthcare workers and people who get tattoos and piercing on their skin. Management of this infection is intended to eradicate it out of the body of patients. Management includes examining the treatment(efficacy and protection), assessment of hepatic condition before commencing therapy, controlling the parameters upon which dual and triple therapies work, monitoring the body after treatment and adjusting the co-factors. Examining the treatment in some special groups of people(HIV/HCV co-infected, hemodialysis patients, renal transplanted patients).

Hepatitis C treatment in the elderly:New possibilities and controversies towards interferon-free regimens

Due to the progressive aging of the hepatitis C virus(HCV) population which have acquired the infection during its maximum spread after the Second World War, the management of the elderly HCV-infected patient is emerging as a hot topic. Unfortunately, although it is recognized that the progression of HCV-related liver disease gets faster with aging, and that even extrahepatic manifestations of HCV infection are probably worse in the elderly, till now, treatment attempts in this population have been significantly limited by the wellknown contraindications and side effects of interferon(IFN). The arrival of several new anti-HCV drugs, and the possibility to combine them in safe and effective anti-viral regimens, is relighting the hope of a cure for many elderly patients who had been cut out of IFN-based treatments. However, although these new regimens will be certainly more manageable, it should be underscored that IFN-free doesn't mean free from any contraindication or side-effect. Moreover, one issue which promises to become central is that of the possible interactions between antiviral therapy and the multiple drugs frequently assumed by elderly patients because of comorbidities. In this review, we will revise the epidemiology pointing to HCV as an infection of the elderly, the evidences that HCV harms the health of the aged patient more than that of the young one, and the available experiences of HCV treatment in the elderly with the "old" IFN-based regimens and with the newer drugs. We will conclude that the availability of IFNfree regimens should prompt us to change our mind and consider a significantly larger number of possible candidates among elderly patients, who would take significant advantage from viral eradication. Rather than the anagraphic age, drug-drug interactions and, mainly in case of economic restrictions, an evaluation of life expectancy dependent on liver disease with respect to that dependent on comorbidities, are likely to be the key issues guiding treatment indication in the next future. The sooner we will change our mind with respect to an a priori obstacle for anti-HCV treatment in the elderly, the sooner we will begin to spare many aged HCV patients from avoidable liver-related complications.

抗丙型肝炎病毒新药波普瑞韦和替拉瑞韦

波普瑞韦(boceprevir,BOC)和替拉瑞韦(telaprevir,TVR)均为丙型肝炎病毒NS3/4A丝氨酸蛋白酶抑制剂,用于治疗基因1型慢性丙型病毒性肝炎(chronic hepatitis C,CHC)。与现行的CHC的标准治疗方案比较,BOC或TVR联合聚乙二醇干扰素α和利巴韦林的三联疗法可大大提高初治病人的持久病毒应答率,且对既往聚乙二醇干扰素α联合利巴韦林治疗无效的病人也有较好的疗效。BOC和TVR的三联疗法比现行的标准治疗方案有更好的疗效和安全性。可以说,BOC和TVR的临床应用,使基因1型CHC的治疗进入新纪元。

特拉匹韦关键中间体{(1S,3AR,6AS)-八氢环戊并[c]吡咯-1-羧酸}的合成

设计了一条合成特拉匹韦重要中间体(1S,3AR,6AS)-八氢环戊并[c]吡咯-1-羧酸(8)的新路线。以4-甲基-5-咪唑基乙醇为原料,经N-烃化、串联加成环化、羰基还原、氨基保护和酯水解等8步反应合成8,总收率24.7%,其结构经1H NMR和MS确证。

基因型1型慢性丙型肝炎的新的标准治疗方案

目的:慢性丙型肝炎是严重的公共卫生问题。近年来,抗丙型肝炎病毒药物有了新的发展,相关治疗指南也有相应更新,故有必要介绍这些重要的进展。方法:进行文献检索,对抗病毒药物的研究进展进行综述。结果:已有两个直接作用的抗病毒药物即博赛泼维和特拉泼维进入临床应用,并被推荐联合聚乙二醇α-干扰素和利巴韦林作为治疗基因型1型慢性丙型肝炎的新的标准治疗方案。结论:研究提示,现有的聚乙二醇α-干扰素联合利巴韦林的标准治疗方案再联合博赛泼维或特拉泼维已成为基因型1型慢性丙型肝炎的新的标准治疗方案。