Researches from Pao-Chien Hospital Reports on Finding in Chronic Hepatitis B Virus Treatment with Nucleos(t)ide Analogue

口服核苷酸類似物對於治療慢性B型肝炎之療效分析報告：以屏東區域教學醫院資料為例

文士祺(Shi-Chi Wen) ； 郭武憲(Wu-Hsien Kuo) ； 鄭隆致(Lung-Chih Cheng) ； 徐瑞宏(Jui-Hung Hsu)

《寶建醫護與管理雜誌》 12卷2期 (2014/12) Pp. 1-22

https://doi.org/10.29681/PCJHM.201412_12(2).0002

摘要

慢性B型肝炎病毒感染為全球性健康的重要議題。關於病毒的感染複製、自然病史及免疫反應衍生壞死纖維化造成肝硬化、肝癌已被清楚的研究。針對藥物作用機轉，目前已有多種有效的口服抗病毒核苷酸類似藥物：干安能（lamivudine）、干適能（adefovir）、貝樂克（entecavir）、喜必福（telbivudine）、及惠立妥（tenofovir）已經被衛生署核准用來治療慢性B型肝炎。本研究以屏東某區域教學醫院胃腸科為對象，利用SPSS12.0作為資料處理及統計分析，分析不同病患特性對藥物療效的影響比較，找出影響成功因素，進而提出因應策略，作為日後個別化病患選用最適合藥物的參考依據。研究顯示，無論在一年後病毒偵測不到、肝功能ALT正常，或是三年後e抗原成功轉換成陰性治療目標上，24週後病毒量偵測為0IU/ml，將是一個可靠有效的預測指標。而在HBeAg陰性患者，有比較高的機會在治療24週後使病毒量降至200IU/ml以下。

並列摘要

Background and Aims: chronic infection with hepatitis B virus (HBV) is a major public health problem worldwide. Potential effective direct antivirus agents such as nucleos(t)ide analogues and the accumulation of substantial experience in the use of these drugs have lead to better therapeutic strategies for chronic HBV infection. The significance of HBV-DNA suppression in predicting long term outcome needs further investigation. Methods: Retrospective study of 139 participants with HBeAg-positive or negative, cirrhosis or none cirrhosis, we determined the rates of HBV-DNA undetectablity, ALT normalization, HBeAg seroconversion, HBsAg loss, reduction of HBV-DNA levels, virus breakthrough, relapse, and occurrence of hepatocellular carcinoma for treatment naïve or retreatment on various nucleos(t)ide analogues for 3 years. The significances of predictive values of baseline factors and easy on-treatment virological and biochemical response have been analyzed. We also employed multivariate analyses to strengthen the positive predictive factors and identify optimal patients who would benefit more from the treatment. Results: A total 139 adult patients with a median age of 52.6(30-84) had proportion with male sex (79.9%), cirrhosis (36%), HBeAg-negative (69.8%), treatment naïve (85.6%). Overall, 97 patients were treated with Entecavir therapy, 23 with Tenofovir, 16 with Telbivuldine, and 3 with Lamivudine. Overall, the HBV-DNA undetectability at 1 year was 69.1%, the ALT normalization at 1 year was 81.3%, the HBeAg-seroconversion at 3 years was 33.3%, HBsAg loss was 0%, the relapse was 27.5%, and the breakthrough was 3.6%. The baseline mean serum HBV-DNA levels was 6.02±1.6 log IU/mL, the mean reduction in serum HBV-DNA level was 5.0±1.5 log IU/mL, baseline ALT level was 274.2±367.9 IU/mL, ALT normalization from 3, 6, 12 months were 47%, 19.4%, 15.8%, respectively. The proportion of residual HBV-DNA levels at 24 weeks was ＜200 IU/mL (78.4%); 0 IU/mL (56.1%), ＜2000 IU/mL (30.9%), respectively. Of all the patients treated with nucleos(t)ide analogues did not differ between baseline and on-treatment factors. The greater proportion of patients with tenofovir treatment was in one group with ALT ＞5xUNL (10.1%), and entecavir treatment in another one with ALT＜5xUNL (48.2%). These elevated baseline HBV-DNA levels were associated with young age, increased serum ALT levels, HBeAg-seropositivity, none liver cirrhosis at study entry. Patients with cirrhosis was associated older age, decreased serum ALT levels, decreased baseline HBV-DNA level, lower reduction of HBV-DNA levels and high risk of hepatocellular carcinoma occurrence. Patient with HBeAg-seronegativity were associated with older age, decreased baseline HBV-DNA levels, lower reduction of HBV-DNA levels, and treatment-naïve. Patients with treatment naïve were associated with older age, decreased serum ALT levels, decreased baseline HBV-DNA levels, and HBeAg-seronegativity. Normalization of ALT levels was associated with lower HBV-DNA levels after 24 weeks treatment, higher viral suppression after one year treatment, and high reduction of HBV-DNA levels. HBV-DNA undetectable after one year treatment was associated with lower HBV-DNA levels at week 24 with 0 IU/mL, ＜2000 IU/mL, and ＜200 IU/mL respectively, HBeAg-seronegativity, normalization of ALT levels at year 1, month 3, month 6 respectively, and old age ＞65 years old. Independent predictors of ALT values normalization at 1 year was HBV-DNA levels undetectable (hazard ratio, 0.313; 95% confidence interval, 0.105-0.935; p=0.002), and reduction of HBV-DNA levels (hazard ratio, 0.645; 95% confidence level, 0.453-0.920). An independent predictor of HBV-DNA level undetectable at 1 year was early response to HBV-DNA level= 0 IU/mL at 24 weeks (hazard ratio, 0.007; 95% confident interval, 0.001-0.089; p=0.000). Independent predictor of HBV-DNA level ＜200 IU/mL was HBeAg-negative (hazard ratio, 0.265; 95% confidence interval, 0.111-0.634; p=0.003). Independent predictor of HBeAg seroconversion at 3 years was HBV-DNA levels undetectable at 1 year according to this higher Wald values. Conclusion: Continuous oral nucleos(t)ide analogues results in improving biochemical and virological outcomes. Undetectable HBV-DNA at 24 weeks was predictive of viral suppression at 1 year, ALT normalization at 1 year, and HBeAg seroconversion at 3 years. Week 24 HBV-DNA level of ＜200 IU/mL was predictive of favorable long-term outcome in patients with HBeAg-negative.

並列關鍵字

HBV ； Chronic hepatitis B ； Nucleoside analogues ； Nucleotide analogues ； Fibrosis ； Durability ； Sustain response ； Virological relapse ； Virological breakthrough ； HBeAg seroconversion ； Biochemical response