Optimizing Treatment for Chronic Hepatitis C Patients with Hepatitis C Virus Genotype 1 Infection

• Main Authors: Chen-Hua Liu, 劉振驊
• Other Authors: Jia-Horng Kao
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/16276864205464839418

博士 === 國立臺灣大學 === 臨床醫學研究所 === 103 === 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-naïve 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.