慢性C型肝炎病毒基因型第一型病患之優化治療

Abstract

慢性C型肝炎病毒 (HCV) 感染為造全球成肝硬化、肝臟代償失調、及肝癌的主要致病原因。據估計全世界約有3%的人口(約1.8億)正感染了C型肝炎病毒。長效型干擾素 (PEG-IFN) 合併雷巴威林 (RBV)為慢性C型肝炎的標準療法之一。慢性C型肝炎病毒基因型第一型之西方病患接受為期48週的合併治療，其持續性病毒反應 (SVR，定義為治療結束後第24週血清中以高敏感度病毒檢測為偵測不到)約為50%。 許多治療前的因子，例如病患年齡、性別、身體質量指數、胰島素抗性、肝臟脂肪化、肝臟纖維化、人種、起始病毒數皆與持續性病毒反應有關。此外先前研究亦顯示治療後第4週以及第12週的病毒下降幅度可預測持續性病毒反應。然而其他治療前以及治療中因子，例如人類介白質28B之基因多形性 (rs8099917以及rs12979860)與治療後第8週病毒下降幅度是否可進一步協助判斷最適切之療程仍需做研究。吾人因此針對慢性C型肝炎病毒基因型第一型的亞洲困難治療族群從事臨床研並探討人類介白質28B基因多形性在此族群所扮演之角色。 目標一: 以長效型干擾素合併雷巴威林治療慢性C型肝炎病毒基因型第一型亞洲病患 長效型干擾素合併雷巴威林治療為慢性C型肝炎病毒基因型第一型的病患的標準療法之一。然而先前研究顯示慢性C型肝炎病毒基因型第一型亞洲病患接受24週的合併治療與慢性C型肝炎病毒基因型第一型西方病患接受48週的合併治療其持續性病毒反應率(SVR)相當。吾人則試圖證明慢性C型肝炎病毒基因型第一型的亞洲病患若接受為期48週的合併治療是否較為期24週的合併治療效果為佳。本研究共收集308位慢性C型肝炎病毒基因型第一型的亞洲病患隨機接受為期24週或48週之合併治療。整體而言，病患接受為期48週的合併治療其持續性病毒反應較病患接受為期24週的合併治療為佳(76%比56%, p < 0.001)。病患若為低起始病毒數(小於800,000 IU/mL)且達到快速病毒反應(RVR, 於治療後第4週血清中以高敏感度病毒檢測為偵測不到)可接受短療程之合併治療而不會減低持續性病毒反應率。然而病患若為高起始病毒數(大於800,000 IU/mL)且無法達到快速病毒反應則應接受標準療程之合併治療以維持良好的持續性病毒反應率。吾人根據以上試驗結果總結C型肝炎病毒基因型第一型的亞洲病患接受為期48週的合併治療較為期24週的合併治療效果為佳，此外治療後第4週之早期病毒動力學反應為決定適切治療療程之重要因子。 目標二: 以長效型干擾素合併雷巴威林治療慢性C型肝炎病毒基因型第一型延遲病毒反應之病患 對於慢性C型肝炎病毒基因型第一型經長效型干擾素合併雷巴威林治療屬於延遲病毒反應之病患，以為期72週的治療或能增加持續性病毒反應。吾人則試圖證明慢性C型肝炎病毒基因型第一型未達快速病毒反應之病患若接受為期72週的合併治療是否較為期48週的合併治療效果為佳。本研究共收集325位慢性C型肝炎病毒基因型第一型未達快速病毒反應之病患進行隨機接受為期48週或72週之合併治療。分析治療後第8週及第12週血清病毒數與持續性病毒反應之關聯。整體而言，病患接受為期72週的合併治療其持續性病毒反應較病患接受為期48週的合併治療為佳(62%比52%, p = 0.03)。病患若於首次於治療後第8週血清中以高敏感度病毒檢測為陰性反應時可接受為期48週的合併治療而不會減低持續性病毒反應率。反之若病患若於首次於治療後第12週血清中以高敏感度病毒檢測為偵測不到時則應接受為期72週的合併治療以維持良好的持續性病毒反應率。吾人根據以上試驗結果總結慢性C型肝炎病毒基因型第一型未達快速病毒反應之病患接受為期72週的合併治療較為期48週的合併治療效果為佳，此外治療後第8週以及第12週之病毒動力學反應為決定適切治療療程之重要因子。 目標三: 慢性C型肝炎病毒基因型第一型病患經長效型干擾素合併雷巴威林治療後達成快速病毒反應時，人類介白質28B基因多形性與持續性病毒反應之關聯 人類介白質28B基因多型性與C型肝炎病毒因子可預測慢性C型肝炎病毒基因型第一型病患接受48週長效型干擾素合併雷巴威林治療之持續性病毒反應。然而人類介白質28B基因多形性能否預測慢性C型肝炎病毒基因型第一型病患接受24週長效型干擾素合併雷巴威林治療之持續性病毒反應仍不清楚。本研究共收集662位慢性C型肝炎病毒基因型第一型病患接受為期24週或48週長效型干擾素合併雷巴威林治療。分析治療前人口學資料、C型肝炎病毒量、人類介白質28B基因多型性 (rs8099917) 、治療時間以及快速病毒反應等因子與持續性病毒反應之關聯。結果顯示介白質28B基因rs8099917 TT多形性、低起始病毒量(小於600,000 IU/mL)、快速病毒反應、以及48週長效型干擾素合併雷巴威林治療分別獨立預測持續性病毒反應。當病患具有介白質28B基因rs8099917 TT多形性及達成快速病毒反應時，病患若為低起始病毒量時則病患接受24週或48週長效型干擾素合併雷巴威林治療之持續性病毒反應相仿(分別為95%及99%);然而病患若為高起始病毒量時則病患接受48週長效型干擾素合併雷巴威林治療之持續性病毒反應較24週治療為佳(分別為97%及70%)。根據以上試驗結果，吾人總結慢性C型肝炎病毒基因型第一型病患若同時具有介白質28B基因rs8099917 TT多型形性、低起始病毒量(小於600,000 IU/mL) 、以及快速病毒反應時可以接受24週長效型干擾素合併雷巴威林治療之短療程治療而不減低持續性病毒反應。 目標四: 慢性C型肝炎病毒基因型第一型病患經長效型干擾素合併雷巴威林治療後未達成快速病毒反應時，人類介白質28B基因多形性與持續性病毒反應之關聯 目標二結論顯示慢性C型肝炎病毒基因型第一型病患經長效型干擾素合併雷巴威林治療後未達成快速病毒反應時，治療後第8週及第12週治療中病毒下降的趨勢是決定患者能否達成持續性病毒反應之重要因子。然而人類介白質28B基因多形性可否幫助吾人確 認此類病患應接受48週或72週之長效型干擾素合併雷巴威林治療仍未明瞭。本研究共收集289位未達成快速病毒反應之慢性C型肝炎病毒基因型第一型病患接受48週或72週長效型干擾素合併雷巴威林治療，針對接受大於80%之藥物療程及劑量，且具有停藥後確切持續性病毒反應結果之病患進行分析。當治療第8週血清中以高敏感度病毒檢測為偵測不到時，病患不論介白質28B基因多形性， 48週或72週之合併治療其持續性病毒反應相當(75-88%)。然而若治療第8週血清中以高敏感度病毒檢測為陽性反應而治療第12週血清中以高敏感度病毒檢測為偵測不到時，病患不論介白質28B基因多形性，72週合併治療之持續性病毒反應均較48週治療為佳(91-100%對13-44%)。根據試驗結果，吾人總結慢性C型肝炎病毒基因型第一型病患經長效型干擾素合併雷巴威林治療後未達成快速病毒反應時，治療後第8週及第12週治療中病毒下降的趨勢才是決定最適切療程的重要因子。

Chronic hepatitis C virus (HCV) infection, the leading cause of cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC), affects approximately 3% of the individuals worldwide. Peginterferon (PEG-IFN) plus ribavirin (RBV) therapy (PR) is one of the current standard of care (SOC) regimens for chronic hepatitis C (CHC), especially is the Asia-Pacific region, with the overall sustained virologic response (SVR) rates of about 50% in HCV genotype 1 (HCV-1) Western patients who receive 48 weeks of treatment. Many pretreatment factors, including age, gender, body mass index (BMI), insulin resistance, hepatic steatosis/fibrosis, ethnicity, and viral load, are associated with SVR. Furthermore, previous studies showed that the viral decline at week 4 and 12 of PR therapy is highly predictive of SVR. However, whether other pretreatment and on-treatment factors, including the single nucleotide polymorphisms (SNPs) near the interleukin 28B (IL28B) gene (rs8099917 and rs12979860) and the week 8 viral decline could further help decide the optimal treatment duration deserve further studies. In this thesis, we therefore investigated the personalized therapy for HCV-1 Taiwanese patients based on treatment duration and early virokinetics. In addition, the role of IL28B in predicting SVR in HCV-1 patients who receive combination therapy was also examined. Aim 1: Peginterferon and ribavirin combination therapy for chronic HCV-1 Asian patients Combination therapy with PR has been one of the current SOC regimens to treat chronic HCV-1 patients. However, previous studies showed that Asian HCV-1 patients with 24 weeks of combination therapy could achieve comparable SVR rates to Western HCV-1 patients with 48 weeks of treatment. In this part, we aimed to evaluate if 48 weeks of PR therapy further improve the overall SVR rate than 24 weeks of PR therapy in Asian chronic HCV-1 patients. We enrolled 308 HCV-1 Asian patients and randomly assigned them to receive either 24 or 48 weeks of combination therapy. The overall SVR rate in patients with 48 weeks of therapy was superior to that in patients with 24 weeks of therapy (76% vs. 56%, p < 0.001). Patients with low baseline viral load (< 800,000 IU/mL) and rapid virologic response (RVR) could achieve a high SVR rate even by truncated duration of therapy. Patients with high viral load (≥ 800,000 IU/mL) or without RVR should receive 48-week therapy to secure the high SVR rate. We concluded that Asian HCV-1 patients had better treatment responses to Western HCV-1 patients by the combination therapy, and the early virokinetics were important to decide the optimal treatment duration. Aim 2: Peginterferon and ribavirin combination therapy for chronic HCV-1 patients with slow viral response PEG-IFN and RBV for 72 weeks has been shown to improve sustained virologic response (SVR) in hepatitis C genotype 1 (HCV-1) slow viral responders. Treatment-na&iuml;ve Asian HCV-1 patients who failed to achieve RVR were randomly assigned to receive 48 (n = 168) or 72 (n = 167) weeks of PR therapy. On-treatment virologic responses at week 8 and 12 of therapy were evaluated for SVR. The SVR rate in patients with 72 weeks of treatment was higher than that in those with 48 weeks of treatment (65% vs. 52%, p = 0.03). Patients who achieved undetectable HCV RNA at week 8 could receive 48 weeks of treatment without compromising the SVR rate. In contrast, patients who achieved undetectable HCV RNA at week 12 should receive 72 weeks of therapy to secure the SVR rate. We concluded that extending the treatment duration to 72 weeks could benefit HCV-1 Asian patients with slow viral response, and on-treatment viral kinetics at week 8 and 12 of PR therapy were key determinants for the optimal treatment duration. Aim 3: The role of IL28B genotype in identifying RVR-positive chronic HCV-1 patients who could receive a truncated duration of peginterferon and ribavirin therapy IL28B single nucleotide polymorphisms (SNP) and viral factors can predict SVR in HCV-1 patients receiving 48 weeks of PR therapy. Whether these factors would identify patients who benefit from shorter duration of therapy remain unclear. A total of 662 HCV-1 patients receiving 24 or 48 weeks of combination therapy were enrolled. Baseline demographic data, HCV viral load, IL28B genotype (rs8099917), duration of therapy, and RVR were evaluated to predict SVR. The SVR rates were further stratified and compared by the independent factors. The IL28B rs8099917 TT genotype, low baseline viral load (HCV RNA ≤ 600,000 IU/mL), RVR and 48-week therapy independently predicted SVR. In RVR patients with IL28B rs8099917 TT genotype, the SVR rate of 24-week therapy was comparable to 48-week therapy (95% vs. 99%) at low baseline viral load, but was inferior to 48-week therapy (70% vs. 97%) at high baseline viral load. We concluded that HCV-1 patients simultaneously bearing IL28B rs8099917 TT genotype, low baseline viral load and rapid virologic response may receive a shorter duration of combination therapy. Aim 4: The role of IL28B in determining optimal PR treatment duration for RVR-negative chronic HCV-1 patients Viral decline at weeks 8 and 12 of PR therapy is an important on-treatment factor for chronic HCV-1 patients who fail to achieve an RVR. Whether IL28B genotype could further identify these patients who benefit from 48 or 72 weeks of PR therapy remains unclear. IL28B and on-treatment virologic responses at week 8 and 12 of PR therapy were evaluated for SVR in 289 compliant patients who received ≥ 80% of drug dosages and treatment duration, and had the end of follow-up viral response. The stratified SVR rates for independent factors were compared by treatment duration. In week-8 viral response (Wk-8R, undetectable HCV RNA at week-8 treatment) patients, the SVR rates of 72-week and 48-week treatment were similar (75-88%), regardless of IL28B genotype or cirrhosis. In non Wk-8R patients who achieved cEVR, the SVR rate of 72-week treatment was higher than that of 48-week treatment for non-cirrhotic patients, regardless of IL28B genotype (91-100% vs. 13-44%). We concluded that although IL28B genotype could predict SVR, it played a minor role when on-treatment viral responses are taken into consideration. On-treatment viral responses at week 8 and 12 were the key determinants to decide the optimal treatment duration in HCV-1 patients without RVR.