奥姆比他韦/帕利他韦/利托那韦+利巴韦林联合治疗基因4型丙型肝炎病毒感染患者的现实实践:多中心经验

B. Aygen, N. Demirtürk, Orhan Yıldız, I. Çelik, Deniz Kamalak, G. Ersöz, A. Batırel, B. Ormen, F. Karakeçili, P. Korkmaz, N. Tuna, A. Şener, R. Çetinkaya, Emine Türkoğlu, Güliz Evik, N. Türker, U. Binay, E. Yenilmez, G. Zararsiz
{"title":"奥姆比他韦/帕利他韦/利托那韦+利巴韦林联合治疗基因4型丙型肝炎病毒感染患者的现实实践:多中心经验","authors":"B. Aygen, N. Demirtürk, Orhan Yıldız, I. Çelik, Deniz Kamalak, G. Ersöz, A. Batırel, B. Ormen, F. Karakeçili, P. Korkmaz, N. Tuna, A. Şener, R. Çetinkaya, Emine Türkoğlu, Güliz Evik, N. Türker, U. Binay, E. Yenilmez, G. Zararsiz","doi":"10.36519/idcm.2019.19014","DOIUrl":null,"url":null,"abstract":"Objective: Objective: Ombitasvir/paritaprevir/ritonavir (OMV/PTV/r) + ribavirin (RBV) combination improved the efficacy, safety, and tolerability of the treatment of chronic hepatitis C virus (HCV) genotype 4 infection. We described the effectiveness and safety of OMV/PTV/r + RBV therapy in patients with genotype 4 infection. Materials and Methods: In this prospective cohort study, HCV genotype 4-infected patients treated with OMV/PTV/r + RBV (n=55) who were registered in a national database were included. Study patients were treatment-naïve or interferon plus RBV-experienced with or without compensated cirrhosis. Demographic, clinical and virological data were analyzed. Details of clinical and laboratory adverse events (AEs) were recorded. Results: The mean age of the patients was 55.2, and 52.7% were male. The majority of patients were non-cirrhotic (81.8%), and 69.1% were treatment-naïve. The HCV RNA level was below 800.000 IU/mL in 16 of the cases. Seventy-eight percent of the patients had an underlying disease. SVR12 rate was 98% in all patients. One patient had virological failure. HCV RNA was undetectable at treatment week 4 in 77.6%, at treatment week 8 in 100%, and at end of treatment in 98%. The SVR12 rates were 100% and 88.9% for those without or with compensated cirrhosis (p= 0.176). Rates of AEs and AEsassociated treatment discontinuation were 69.1% and 3.6% in the patients, respectively. Conclusion: The OBV/PTV/r + RBV combination was found to have high efficacy and safety profile in the patients with chronic HCV genotype 4 infection. This work is licensed under a Creative Commons Attribution-Non Commercial 4.0 International License. 98 Treatment of Chronic HCV Genotype 4 Infection Aygen et al. INTRODUCTION A bout 170-200 million people are known to be infected with the hepatitis C virus (HCV) worldwide. Chronic hepatitis C (CHC) infection carries risks of hepatic fibrosis, cirrhosis, portal hypertension, liver failure, and hepatocellular carcinoma (HCC) (1-4). Chronic HCV infection is an important health problem in Turkey (5-10). In Turkey, among HCV infections, genotype 1b was reported to be the most common one (90%), while types 2, 3, and 4 exist, with lower prevalence. However, recently, there has been an increase in HCV genotype 4 infections in Turkey (9-13). Two studies from Kayseri reported an unusually high proportion of genotype 4 infections reaching up to 35% among the patients, who were admitted to the hospitals for treatment of CHC (14, 15). This high proportion was significantly higher than the average prevalence of 1.4% reported for type 4 HCV infections in Turkey (15). It was shown recently that Kayseri genotype 4 isolates were closely related to subtype 4d sequences (13, 16). There are several different treatment approaches for HCV genotype 4 infection. By the combination therapy of pegylated interferon (PegINF) and ribavirin (RBV), the sustained virological response (SVR) rate was 60% in patients infected with HCV genotype 4 (17). First-generation protease inhibitors in combination with PegINF and RBV achieved low rates of response in the patients infected with HCV genotype 4, and these regimens were characterised by less favourable safety profiles, which affect adherence to the PegINF-based therapy (7, 11, 12). The novel INF-free second-generation direct-acting antivirals (DAAs) therapy consisting of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) ± dasabuvir (DSV) ± RBV improved the efficacy, safety, and tolerability of the treatment of chronic HCV infection. This combination has also proved effective not only in genotype 1 but also in genotype 4. Patients with genotype 4 infection were recommended to be treated with the combination of OBV/PTV/r + RBV, which also resulted in high SVR rates in clinical and real-world trials (18-22). Three of these medications target HCV at different phases of the viral life cycle. Two of them were protease inhibitors: OBV inhibits viral NS5A phosphoprotein, which was involved in virus assembly and PTV inhibited viral NS3-4A serine protease involved in proteolytic processing. Furthermore, ritonavir enhances the pharmacokinetic properties of PTV, increasing their availability through improved drug exposure (23). We aimed to assess the efficacy and safety of OMV/ PTV/r + RBV combination in genotype 4 infected patients in real clinical practice. MATERIALS AND METHODS Study population The patients older than 18 years, with chronic HCV genotype 4 infection, treatment-naïve or previously treated with PegINF/RBV, and chronic hepatitis or compensated cirrhosis were included in the study. The patients with genotype non-4 HCV infection, decompensated liver cirrhosis with Child-Pugh class B or C, evidence of HCC, a concomitant medication that was contraindicated according to manufacturer’s recommendations, current pregnancy, lactation, and platelets count <25.000/mm3 were excluded. We enrolled patients for treatment with OBV/PTV/r + RBV according to the therapeutic guidelines of the National Health Application Notice of the Ministry of Health (24). The clinical information about baseline demographic characteristics, prior treatment status, baseline viral load, liver function tests [bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin], haemoglobin, platelets count, international normalized ratio • There is an increase in HCV genotype 4 infection in Turkey. The regimen of OBV/PTV/r + DSV ± RBV was highly efficacious to treat HCV genotype 4 infection, including patients with compensated cirrhosis. • The patients with chronic HCV genotype 4 infection who were treated with OBV/PTV/r + RBV for 12 weeks achieved 98% SVR12 in our study. Adverse events were mostly mild and did not require medical intervention This cohort is the first to present real-life data in our country. 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Zararsiz\",\"doi\":\"10.36519/idcm.2019.19014\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Objective: Objective: Ombitasvir/paritaprevir/ritonavir (OMV/PTV/r) + ribavirin (RBV) combination improved the efficacy, safety, and tolerability of the treatment of chronic hepatitis C virus (HCV) genotype 4 infection. We described the effectiveness and safety of OMV/PTV/r + RBV therapy in patients with genotype 4 infection. Materials and Methods: In this prospective cohort study, HCV genotype 4-infected patients treated with OMV/PTV/r + RBV (n=55) who were registered in a national database were included. Study patients were treatment-naïve or interferon plus RBV-experienced with or without compensated cirrhosis. Demographic, clinical and virological data were analyzed. Details of clinical and laboratory adverse events (AEs) were recorded. Results: The mean age of the patients was 55.2, and 52.7% were male. The majority of patients were non-cirrhotic (81.8%), and 69.1% were treatment-naïve. The HCV RNA level was below 800.000 IU/mL in 16 of the cases. Seventy-eight percent of the patients had an underlying disease. SVR12 rate was 98% in all patients. One patient had virological failure. HCV RNA was undetectable at treatment week 4 in 77.6%, at treatment week 8 in 100%, and at end of treatment in 98%. The SVR12 rates were 100% and 88.9% for those without or with compensated cirrhosis (p= 0.176). Rates of AEs and AEsassociated treatment discontinuation were 69.1% and 3.6% in the patients, respectively. Conclusion: The OBV/PTV/r + RBV combination was found to have high efficacy and safety profile in the patients with chronic HCV genotype 4 infection. This work is licensed under a Creative Commons Attribution-Non Commercial 4.0 International License. 98 Treatment of Chronic HCV Genotype 4 Infection Aygen et al. INTRODUCTION A bout 170-200 million people are known to be infected with the hepatitis C virus (HCV) worldwide. 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By the combination therapy of pegylated interferon (PegINF) and ribavirin (RBV), the sustained virological response (SVR) rate was 60% in patients infected with HCV genotype 4 (17). First-generation protease inhibitors in combination with PegINF and RBV achieved low rates of response in the patients infected with HCV genotype 4, and these regimens were characterised by less favourable safety profiles, which affect adherence to the PegINF-based therapy (7, 11, 12). The novel INF-free second-generation direct-acting antivirals (DAAs) therapy consisting of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) ± dasabuvir (DSV) ± RBV improved the efficacy, safety, and tolerability of the treatment of chronic HCV infection. This combination has also proved effective not only in genotype 1 but also in genotype 4. 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引用次数: 2

摘要

目的:目的:Ombitasvir/paritaprevir/ritonavir (OMV/PTV/r) +利巴韦林(RBV)联合治疗慢性丙型肝炎病毒(HCV)基因4型感染的疗效、安全性和耐受性提高。我们描述了OMV/PTV/r + RBV治疗基因4型感染患者的有效性和安全性。材料和方法:在这项前瞻性队列研究中,纳入了在国家数据库中登记的接受OMV/PTV/r + RBV治疗的HCV基因型4感染患者(n=55)。研究患者为treatment-naïve或干扰素+ rbv,伴有或不伴有代偿性肝硬化。对人口学、临床和病毒学资料进行分析。详细记录临床和实验室不良事件(ae)。结果:患者平均年龄为55.2岁,男性占52.7%。大多数患者为非肝硬化(81.8%),69.1%为treatment-naïve。16例HCV RNA水平低于800.000 IU/mL。78%的患者有潜在疾病。所有患者的SVR12率为98%。一名患者出现病毒学失败。77.6%的患者在治疗第4周检测不到HCV RNA, 100%的患者在治疗第8周检测不到,98%的患者在治疗结束时检测不到HCV RNA。无代偿性肝硬化或代偿性肝硬化患者的SVR12率分别为100%和88.9% (p= 0.176)。ae和aesa相关治疗的停药率分别为69.1%和3.6%。结论:OBV/PTV/r + RBV联合治疗慢性HCV基因型4感染患者具有较高的疗效和安全性。本作品采用知识共享署名-非商业4.0国际许可协议授权。全世界已知约有1.7 -2亿人感染丙型肝炎病毒(HCV)。慢性丙型肝炎(CHC)感染有肝纤维化、肝硬化、门脉高压、肝功能衰竭和肝细胞癌(HCC)的风险(1-4)。慢性丙型肝炎病毒感染是土耳其的一个重要健康问题(5-10)。在土耳其,在HCV感染中,基因1b型报告为最常见的一种(90%),而2、3和4型也存在,患病率较低。然而,最近,土耳其的HCV基因型4感染有所增加(9-13)。来自开塞利的两项研究报告称,在因CHC入院治疗的患者中,基因4型感染的比例异常高,高达35%(14,15)。这一高比例显著高于土耳其报告的4型HCV感染的平均患病率1.4%(15)。最近有研究表明,Kayseri基因型4分离株与4d亚型序列密切相关(13,16)。HCV基因型4感染有几种不同的治疗方法。通过聚乙二醇化干扰素(PegINF)和利巴韦林(RBV)联合治疗,HCV基因型4感染患者的持续病毒学应答(SVR)率为60%(17)。第一代蛋白酶抑制剂联合PegINF和RBV在HCV基因型4感染患者中的应答率较低,而且这些方案的特点是安全性较差,这影响了对PegINF为基础的治疗的依从性(7,11,12)。新型无if的第二代直接作用抗病毒药物(DAAs)由ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r)±dasabuvir (DSV)±RBV组成,提高了治疗慢性HCV感染的疗效、安全性和耐受性。该组合不仅对基因1型有效,对基因4型也有效。基因4型感染患者推荐采用OBV/PTV/r + RBV联合治疗,在临床和实际试验中也导致了较高的SVR率(18-22)。其中三种药物针对HCV病毒生命周期的不同阶段。其中两种为蛋白酶抑制剂:OBV抑制参与病毒组装的病毒NS5A磷酸化蛋白,PTV抑制参与蛋白水解加工的病毒NS3-4A丝氨酸蛋白酶。此外,利托那韦增强了PTV的药代动力学特性,通过改善药物暴露增加了它们的可用性(23)。我们的目的是在实际临床实践中评估OMV/ PTV/r + RBV联合治疗基因4型感染患者的有效性和安全性。研究对象为年龄大于18岁、慢性HCV基因型4感染、treatment-naïve或既往接受过PegINF/RBV治疗、慢性肝炎或代偿性肝硬化的患者。排除基因型非4型HCV感染、Child-Pugh B级或C级失代偿性肝硬化、HCC证据、根据制造商推荐的禁忌用药、当前妊娠、哺乳期和血小板计数<25.000/mm3的患者。
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Ombitasvir/ Paritaprevir/ Ritonavir + Ribavirin Combination Therapy in Hepatitis C Virus Infected Patients with Genotype 4 in Real-life Practice: A Multicentre Experience
Objective: Objective: Ombitasvir/paritaprevir/ritonavir (OMV/PTV/r) + ribavirin (RBV) combination improved the efficacy, safety, and tolerability of the treatment of chronic hepatitis C virus (HCV) genotype 4 infection. We described the effectiveness and safety of OMV/PTV/r + RBV therapy in patients with genotype 4 infection. Materials and Methods: In this prospective cohort study, HCV genotype 4-infected patients treated with OMV/PTV/r + RBV (n=55) who were registered in a national database were included. Study patients were treatment-naïve or interferon plus RBV-experienced with or without compensated cirrhosis. Demographic, clinical and virological data were analyzed. Details of clinical and laboratory adverse events (AEs) were recorded. Results: The mean age of the patients was 55.2, and 52.7% were male. The majority of patients were non-cirrhotic (81.8%), and 69.1% were treatment-naïve. The HCV RNA level was below 800.000 IU/mL in 16 of the cases. Seventy-eight percent of the patients had an underlying disease. SVR12 rate was 98% in all patients. One patient had virological failure. HCV RNA was undetectable at treatment week 4 in 77.6%, at treatment week 8 in 100%, and at end of treatment in 98%. The SVR12 rates were 100% and 88.9% for those without or with compensated cirrhosis (p= 0.176). Rates of AEs and AEsassociated treatment discontinuation were 69.1% and 3.6% in the patients, respectively. Conclusion: The OBV/PTV/r + RBV combination was found to have high efficacy and safety profile in the patients with chronic HCV genotype 4 infection. This work is licensed under a Creative Commons Attribution-Non Commercial 4.0 International License. 98 Treatment of Chronic HCV Genotype 4 Infection Aygen et al. INTRODUCTION A bout 170-200 million people are known to be infected with the hepatitis C virus (HCV) worldwide. Chronic hepatitis C (CHC) infection carries risks of hepatic fibrosis, cirrhosis, portal hypertension, liver failure, and hepatocellular carcinoma (HCC) (1-4). Chronic HCV infection is an important health problem in Turkey (5-10). In Turkey, among HCV infections, genotype 1b was reported to be the most common one (90%), while types 2, 3, and 4 exist, with lower prevalence. However, recently, there has been an increase in HCV genotype 4 infections in Turkey (9-13). Two studies from Kayseri reported an unusually high proportion of genotype 4 infections reaching up to 35% among the patients, who were admitted to the hospitals for treatment of CHC (14, 15). This high proportion was significantly higher than the average prevalence of 1.4% reported for type 4 HCV infections in Turkey (15). It was shown recently that Kayseri genotype 4 isolates were closely related to subtype 4d sequences (13, 16). There are several different treatment approaches for HCV genotype 4 infection. By the combination therapy of pegylated interferon (PegINF) and ribavirin (RBV), the sustained virological response (SVR) rate was 60% in patients infected with HCV genotype 4 (17). First-generation protease inhibitors in combination with PegINF and RBV achieved low rates of response in the patients infected with HCV genotype 4, and these regimens were characterised by less favourable safety profiles, which affect adherence to the PegINF-based therapy (7, 11, 12). The novel INF-free second-generation direct-acting antivirals (DAAs) therapy consisting of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) ± dasabuvir (DSV) ± RBV improved the efficacy, safety, and tolerability of the treatment of chronic HCV infection. This combination has also proved effective not only in genotype 1 but also in genotype 4. Patients with genotype 4 infection were recommended to be treated with the combination of OBV/PTV/r + RBV, which also resulted in high SVR rates in clinical and real-world trials (18-22). Three of these medications target HCV at different phases of the viral life cycle. Two of them were protease inhibitors: OBV inhibits viral NS5A phosphoprotein, which was involved in virus assembly and PTV inhibited viral NS3-4A serine protease involved in proteolytic processing. Furthermore, ritonavir enhances the pharmacokinetic properties of PTV, increasing their availability through improved drug exposure (23). We aimed to assess the efficacy and safety of OMV/ PTV/r + RBV combination in genotype 4 infected patients in real clinical practice. MATERIALS AND METHODS Study population The patients older than 18 years, with chronic HCV genotype 4 infection, treatment-naïve or previously treated with PegINF/RBV, and chronic hepatitis or compensated cirrhosis were included in the study. The patients with genotype non-4 HCV infection, decompensated liver cirrhosis with Child-Pugh class B or C, evidence of HCC, a concomitant medication that was contraindicated according to manufacturer’s recommendations, current pregnancy, lactation, and platelets count <25.000/mm3 were excluded. We enrolled patients for treatment with OBV/PTV/r + RBV according to the therapeutic guidelines of the National Health Application Notice of the Ministry of Health (24). The clinical information about baseline demographic characteristics, prior treatment status, baseline viral load, liver function tests [bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin], haemoglobin, platelets count, international normalized ratio • There is an increase in HCV genotype 4 infection in Turkey. The regimen of OBV/PTV/r + DSV ± RBV was highly efficacious to treat HCV genotype 4 infection, including patients with compensated cirrhosis. • The patients with chronic HCV genotype 4 infection who were treated with OBV/PTV/r + RBV for 12 weeks achieved 98% SVR12 in our study. Adverse events were mostly mild and did not require medical intervention This cohort is the first to present real-life data in our country. HIGHLIGHTS
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