The Impact of HBeAg Index Value on the Response to Lamivudine Treatment in Chronic Hepatitis B Patients

背景： B型肝炎病毒e抗原陽性之慢性B型肝炎病患，如有持續或間歇性肝指數上昇，且大於正常值上限的二倍，可先觀察3-6個月，若無自發性的e抗原血清轉換，之後可考慮給予治療。對於干安能(Lamivudine)的療效方面，亞洲多中心研究顯示e抗原血清陰轉率與干安能治療的期間成正比，干安能治療一年至四年的反應率分別為17%，27%，33%和47%，治療前丙胺酸轉胺酶(ALT)值與干安能治療的反應率呈正相關，其他相關的因子包括B型肝炎病毒基因型和組織肝炎活性指數，然而e抗原效價和治療中e抗原效價下降的速度與治療反應是否相關，目前並不清楚。 目的： 針對e抗原陽性的慢性B型肝炎病患，探討e抗原效價與干安能治療反應是否相關。假設一，B型肝炎e抗原效價和B型肝炎病毒去氧核醣核酸值是否相關。假設二，治療前的e抗原效價，治療中e抗原效價的動態變化，與治療的反應是否相關。 方法： 本計劃共收集49位e抗原陽性慢性B型肝炎病患，且丙胺酸轉胺酶(ALT)值大於200 IU/L，其他原因之肝炎，合併肝硬化及肝癌排除在外。給予每天100毫克的干安能治療一年，干安能治療合併反應的定義為：丙胺酸轉胺酶(ALT)正常(<40 IU/L)，e抗原消失，且B型肝炎病毒去氧核醣核酸(HBV DNA)用傳統雜交檢測(hybridization)偵測不到(即<1x105 copies/ml)，於病患治療滿一年時，依其治療反應與否分為兩組，比較其治療前的e抗原效價和治療中e抗原效價下降的速度與治療反應是否相關。 結果: 49位病患中，男性35位，女性14位，平均年齡為31.0+7.3歲，B型肝炎病毒基因型B有37位(75.5%)，基因型C有12位(24.5%)，平均治療前的丙胺酸轉胺酶(ALT)值為565.7+433.8IU/L，e抗原效價(S/N值)為38.5+41.8，B型肝炎病毒去氧核醣核酸(HBV DNA)值為3.85x109 +1.1x1010copies/ml，依ALT值分為兩組，一組丙胺酸轉胺酶(ALT)值介於正常值上限5倍到10倍之間，共有24位(49%)，另一組丙胺酸轉胺酶(ALT)值大於正常值上限10倍，共有25位(51%)。其中24位病患之干安能治療已滿一年，平均年齡為32.9±7.03歲，男性19位，女性5 位，其干安能治療一年的反應如下:生化反應共19位(79.2%)，病毒反應共14位(58.3%)，血清反應共18位(75%)，合併反應共12位(50%)。治療前的基本資料於B型肝炎病毒基因型B者和基因型C間做比較，兩組病患在年齡，性別，丙胺酸轉胺酶(ALT)值，凝血酶原時間(Prothrombin time)延長值，總膽紅素值(Total bilirubin)，血小板值，e抗原效價，B型肝炎病毒去氧核醣核酸(HBV DNA)值均無顯著差異。丙胺酸轉胺酶(ALT)值大於正常值上限10倍組和丙胺酸轉胺酶(ALT)值介於正常值上限5倍到10倍組做比較，兩組病患在年齡，性別，基因型，凝血酶原時間延長值，血小板值，e抗原效價，B型肝炎病毒去氧核醣核酸(HBV DNA)值均無顯著差異。丙胺酸轉胺酶(ALT)值大於正常值上限10倍組的總膽紅素值和凝血酶原時間延長值略高(P=0.06和0.09)，但未達統計上顯著意義。其中33位病患用藥前的B型肝炎病毒去氧核醣核酸(HBV DNA)值和e抗原效價之比較呈正相關( Pearson correlation coefficient:0.62, P<0.0001 )，具統計上顯著意義。在干安能治療一年之反應上，依合併反應的結果，將病患分為兩組，一組為反應組(Responder)，另一組為無反應組(Non-responder)，兩組病患在年齡，性別，基因型，治療前丙胺酸轉胺酶(ALT)值，凝血酶原時間延長值，總膽紅素值，血小板值，e抗原效價，B型肝炎病毒去氧核醣核酸(HBV DNA)值，第三月和六月早期e抗原反應( EER, early e antigen response) ，第六月e抗原反彈(e antigen rebound)均無顯著差異。 討論和結論: 本研究證實B型肝炎病毒e抗原效價和B型肝炎病毒去氧核醣核酸(HBV DNA)值呈正相關，故在臨床上吾人可用B型肝炎e抗原效價預測病毒去氧核醣核酸(HBV DNA)值，公式為”Log(B型肝炎病毒去氧核醣核酸值)=0.0166 x(B型肝炎病毒e抗原效價)+7.0586”。 B型肝炎病毒基因型B和基因型C患者做比較，兩組病患在e抗原效價和B型肝炎病毒去氧核醣核酸(HBV DNA)值均無顯著差異。每天100毫克的干安能治療一年，血清反應達75%，合併反應達50%。依目前治療完成的病患結果，丙胺酸轉胺酶(ALT)值大於十倍病患組的治療反應和丙胺酸轉胺酶(ALT)值大於五倍病患組相仿(53.8 %和45.5%)。治療前e抗原效價，B型肝炎病毒去氧核醣核酸(HBV DNA)值，第三月和六月早期e抗原反應( EER, early e antigen response) 和六月e抗原反彈(e antigen rebound)均無法預測治療反應。但當49位病患皆完成治療後，因樣本數的增加，有可能會改善統計檢驗之判別力。Background: In Asian multi-center research for lamivudine treatment in patients with chronic hepatitis B, HBeAg seroconversion rate was proportional to the duration of lamivudine treatment. The response rate of lamivudine treatment was 17%, 27%, 33% and 47% from one year to four years treatment respectively. The pretreatment ALT level has been noted to be positively correlated with the response of lamivudine treatment. It is not clear whether the titer of HBeAg can predict the outcome of lamivudine treatment? Aim: Are pretreated and dynamic change of HBeAg titer associated with the response of lamivudine treatment in chronic hepatitis B patients? Methods: Total 49 chronic hepatitis B patients with HBeAg positive and ALT level more than 5 times of normal upper limit without cirrhosis and malignancy were enrolled. They received 100 mg lamivudine every day for at least one year. The response of treatment is defined as normalized ALT level, HBeAg loss or seroconversion and undetectable HBV DNA by traditional hybridization method. According to the response after one year treatment, we separated the persons into two groups: one is response group, another is non-response group. Compare the titer of HBeAg before treatment and the ratio of HBeAg decrease during treatment especially in first three and six months (early HBeAg response) between two groups. Results: Total 49 cases were enrolled. The baseline characters as following: male/female=35/14, mean age 31+7.3 year-old, genotype B: genotype C =37:12(75.5%/24.5%), pretreatment ALT value:565.7U/L±433.8, HBeAg index ratio 38.5±41.8(S/N), HBV DNA titer 3.85x109±1.1×1010 copies/ml. Total 24 cases completed one year lamivudine treatment. The male to female ratio was 19/5 . The mean age was 32.9+7.03 year-old. The one year on-therapy response as following: biochemical response 79.2%, serologic response 75%, virologic response 58.3% and combined response 50%. The baseline characters of genotype B infected chronic hepatitis B patients were comparable with those of genotype C infected patients. The HBeAg titer was positively correlated with HBV DNA titer (Pearson correlation coefficient:0.62, P<0.0001). According to the presence of combined response, the characters of responders were comparable with those of non-responder in age, sex, genotype, pretreated ALT value, HBV DNA titer, HBeAg titer, 3rd and 6th early e antigen response and 6th HBeAg rebound. Discussion and conclusions: In our study, HBeAg index ratio was positively correlated with HBV DNA titer. Therefore, we could predict the HBV DNA titer by HBeAg index ratio in clinical practice. The HBeAg index ratio and HBV DNA titer were comparable between genotype B and genotype C patients. The response rate of one year lamivudine treatment was higher than 50%. According to the data from treatment completed cases, the response rate was similar between the patients whose ALT was between 5 times and 10 times upper normal limit and those whose ALT above 10 times upper normal limit. The baseline HBV DNA titer, HBeAg index ratio, 3rd and 6th early e antigen response and 6th HBeAg rebound could not predict the treatment response. However, when all our patients complete the treatment, it is possible to improve the statistic power due to the increase of case numbers.中文摘要 P 05 緒論 P 08 研究方法與材料 P 18 結果 P 22 討論 P 25 展望 P 30 論文英文簡述 P 31 參考文獻 P 33 圖表 P 41 附錄 P 5