探討口服抗C型肝炎藥物於臨床的實際成效

Abstract

全世界約有七千一百萬人感染C型肝炎病毒。在台灣20歲以上的成人C型肝炎帶原率約為4.4%，亦即近六十萬人為慢性C型肝炎的患者，此外隨年齡增長慢性C型肝炎之盛行率也越高。感染C型肝炎病毒之後約有80%的患者會成為慢性帶原者，其中的20%更會進展為肝硬化。而肝硬化為肝細胞癌的重要危險因子，肝硬化患者每年約有2-5%的機會發展出肝細胞癌。據國民健康署統計，慢性肝炎、肝硬化及肝癌一直以來是國人十大死因前幾名，顯示慢性C型肝炎相關之肝病變對國人健康、生活及社會經濟有很大的影響。 慢性C型肝炎的治療方式從早期的干擾素治療，發展為長效型干擾素結合雷巴威林，治療成效進步至大約四成至五成。然而長效型干擾素結合雷巴威林的治療副作用與禁忌症多，造成許多病人無法完成治療甚至無法接受治療。近年來口服抗病毒藥物的研發，不但大為提高治療成效，且能避免許多副作用。由近年來數個大型臨床試驗得知口服抗病毒藥物的治療效果更勝傳統的以長效型干擾素結合雷巴威林的治療。然而由於口服抗病毒藥物進入台灣時間較晚，對於國人的實際治療效果是否如臨床試驗仍存在許多未知，且每個國家的C型肝炎病毒基因型分佈不同與人種差異，造成實際治療成效未必盡如臨床試驗。因此本回溯性研究期能回答前述問題。 目的: 本回溯性觀察研究期能了解口服抗病毒藥物的實際治療成效與可能之副作用，主要試驗指標為治療後12週的C型肝炎病毒量，達陰性者(Sustained Virologic Response, SVR12)為治療成功個案。另外本研究將與其他國家的臨床效果與先前數個臨床試驗比較其中之異同。再者，從公共衛生層面來看，本研究的結果可以作為未來國內治療慢性C型肝炎的重要參考。 方法: 我們將以於本院定期追蹤的慢性C型肝炎病患建立一完整的資料庫，取得病患於治療前的病史與各項指標，如C型肝炎病毒基因型，病毒量，生化值與全細胞計數等與腹部超音波或肝纖維化掃瞄及相關影像學檢查或肝臟切片的結果，來評估病人肝病的狀態，並於治療中追蹤肝功能與病毒量至治療完成後12週。治療成效依各種不同的口服抗病毒藥物作結果分析。研究策略方面，由於口服C型肝炎藥物目前仍為高貴藥品，全民健保自2017年一月底起有條件的給付，因此實際服用的患者相對並不多，且國內各醫學中心中以本院個案數較多，因此本研究計畫的優勢在於本院有完整且數量較大的病患資料庫，再者本肝炎中心團隊研究能量雄厚，必能有成果發表。研究結果已於2017年的亞太肝臟醫學會年會與台灣消化醫學週發表初步成果，且已投稿中。 結果: 從我們的研究發現，口服抗病毒藥物於慢性C型肝炎的實際治療效果與先前數個重要臨床試驗與其他國家的臨床結果相仿，口服抗病毒藥物於器官移植患者無重大安全疑慮。然而有許多議題仍需更多證據與研究，例如口服抗病毒藥物治療過程中，肝癌的產生或復發、在B型肝炎與C型肝炎共同感染者中，B型肝炎的復發等。

Background: Hepatitis C virus (HCV) infection is one of the leading causes of liver cirrhosis and hepatocellular carcinoma and remains a threat for public health worldwide. Successful HCV eradication lowers the occurrence of liver-related complications and mortality. Conventional therapy with pegylated-IFN and ribavirin may achieve relatively satisfactory response although requires lengthy treatment and are associated with numerous treatment-associated adverse events. The treatment of chronic hepatitis C has entered a new phase since the introduction and development of direct-acting antiviral agents (DAAs) in recent years. The treatment response as well as patient tolerability and adverse effects of DAAs from clinical trials are reported to be superior to those of conventional therapy with pegylated interferon and ribavirin. However, many differences still exist between the settings of real-world practice and clinical trials. So far, most real-world results have been reported consecutively from Western countries, although these data are still limited in Asian countries except Japan and South Korea. Because of distinct genotype distribution as well as ethnic factors, a detailed real-world data from our country is essential which may provide precious information and reference to healthcare providers and public health workers. Aim: To investigate the effectiveness of various DAA regimens in Taiwanese patients with chronic hepatitis C (CHC). Methods: We performed a retrospective study on 400 CHC patients who were followed regularly at our hospital and completed the treatment course. The primary endpoint was undetectable HCV RNA (an HCV RNA level of <25 IU/mL) at 12 weeks post-treatment (SVR12). The outcomes were analyzed in per-protocol analysis. The results were further stratified by different DAA regimens and HCV genotypes. Results: Genotype 1b was the major genotype (297, 74.3%), followed by genotype 2 (65, 16.3%). The patients were treated depending on HCV genotype, previous treatment history, and clinical conditions. The SVR12 rates of 57 patients treated with sofosbuvir and ribavirin, 107 treated with ledipasvir/sofosbuvir with or without ribavirin, 60 treated with daclatasvir/asunaprevir with or without ribavirin, 129 treated with ombitasvir/paritaprevir/ritonavir/dasabuvir with or without ribavirin, 12 treated with sofosbuvir/daclatasvir with or without ribavirin, and 35 treated with elbasvir/grazoprevir were 98.2%, 97.2%, 85.0%, 97.7%, 100.0%, and 100.0%, respectively. No serious adverse events were observed. Among the twelve HBV/HCV dually-infected patients, two patients had acute HBV flare-up during DAA therapy. Moreover, nine patients developed hepatocellular carcinoma during or after the completion of DAA therapy. Conclusions: The overall SVR12 rates in our study cohort who received various DAAs were comparable with those reported in previous pivotal trials and real-world data in other countries. DAAs are safe for treating patients with organ transplants. The interaction of HBV and HCV during DAA therapy as well as the observation of de novo HCC development and HCC recurrence during or after DAA therapy warrants additional studies.