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1、報告人：朱郁芬,A Comparison of Entecavir and Lamivudine for HBeAg-Positive Chronic Hepatitis B,Hepatitis B virus Virology,Partially ds DNA genome, 42nm 4 genes HBsAg, HBcAg, HBV Pol/RT, X protein Serologic marker of HBV infection: HBsAg Serologic markers of HBV replication: HBeAg, HBV DNA, HBV Polymerase,M
2、iddle surface antigen （HBsAg）,Nucleocapsid （HBcAg）,DNA polymerase,Envelope （HBsAg）,Small surface antigen （HBsAg）,Large surface antigen （HBsAg）,Genomic DNA,RNA primer,Hepatitis B virus Virology,HBsAg envelopes,Partially double-stranded DNA,A(n),Infectious HBV virion,(-)-DNA,Infectious HBV virion,mRNA
3、,cccDNA,DNA pol,RT,Encapsidated pregenomic mRNA,Replication cycle for HBV,How HBV cause disease,Acute HBV infection,90% neonates,2530% children,10% adults,Progressive chronic hepatitis,Cirrhosis,HCC,Death,Decompensated cirrhosis,Inactive carrier state,EASL Consensus Guidelines. J Hepatol 2003; Lok,
4、McMahon. Hepatology 2004 (AASLD Guidelines),Chronic infection,1540%,Fulminant hepatic failure,2%,Hepatitis B Progression,Stages of Chronic HBV Infection,Adapted from Fattovich. Sem Liver Dis 2003,The Global Disease,WHO and CDC fact sheets, available at www.who.int and www.cdc.gov,Half of the worlds
5、population lives in an area with high HBV prevalence,Prevalence of chronic HBV carriers in different countries,From: World Health Organization. Introduction of hepatitis B vaccine into childhood immunization services, 2001, Geneva, WHO, WHO/v&B/01.31,HBsAg Endemicity,8% and above High 2% - 8% - Inte
6、rmediate Below 2% - Low,Treatment：Entecavir Lamivudine,HBV study important record,1965 find virus antigen 1970 find virus particle 1973 find polymerase in virus particle 1974 atomic structure for restriction enzyme 1976 treat for IFN- 1977 find -antigen in liver cell 1982 know HBV replication 1986 r
7、eassembled HBV vaccine 1993 Lamivudine clinical try 1999 Lamivudine Approvable 2002 PEG - clinical try 2005 Entecavir Approvable,New Approval Medicine,Interferon Intron A： recombinant interferon -2b ；made by Schering-Plough Nucleotide analogue Lamivudine ；made by GlaxoSmithKline Entecavir； made by B
8、ristol-Myers Squibb Adefovir dipivoxil；made by Gilead Sciences,Intron A,簡介： 使HBV活性減低，降低發生肝硬化、肝癌機會。 作用機制： Interferon由受感染的細胞所產生，刺激其他未受感染的細胞進入抵抗病毒，產生許多antiviral effector molecules，因而改變細胞表面蛋白質抗原的組成，使得細胞不易感染；另一方面受干擾素刺激的細胞會活化RNAse-L，將mRNA分解；還能磷酸化eIF2，降低轉譯的效率，干擾病毒蛋白質的合成。關於其作用機制尚有很多不清楚的地方。 副作用：產生像感冒般的症狀，掉頭髮
9、，情緒不穩定，抑制骨髓造血功能，肝衰竭等等 使用限制：需同時符合以下3項條件 HBsAg（）超過六個月及HBeAg（）超過三個月。 ALT值介於正常值上限五倍以上（ALT5X）。 無肝功能代償不全。,Interferon signal transduction,Adefovir Dipivoxil,簡介：Adefovir原本是一種治療HIV的藥物，後來研究發現對於抑制HBV也有療效。Adefovir可抑制HBV複製，改善肝功能指數及肝組織發炎。 作用機制：進入細胞後，adefovir會直接和HBV的DNA聚合酶結合，抑制HBV的複製。 副作用：極少，產生抗藥性的機率低，但長期服用可能產生腎臟方
10、面的問題,Lamivudine,簡介：Lamivudine是一個化學合成的核苷類似物，本來是用來治療愛滋病毒的，在較低劑量時也能對抗HBV，故而有醫師將之用來治療慢性B型肝炎。 作用機制：可以抑制病毒反轉錄酵素，阻斷病毒DNA的合成而抑制病毒的複製。 副作用：極少，但較易產生抗藥性 可被迅速良好吸收 使用限制：需同時符合以下2項條件 HBsAg（）超過六個月及HBeAg（）超過三個月。 ALT值大於或等於正常值上限五倍以上（ALT5X），或已發生肝代償不全者（有黃膽且凝血酶原時間超過三秒）。,HBsAg envelopes,Partially double-stranded DNA,A(n),
11、Infectious HBV virion,(-)-DNA,Infectious HBV virion,mRNA,cccDNA,DNA pol,RT,Encapsidated pregenomic mRNA,Replication cycle for HBV,Lamivudine,Entecavir,簡介：對HBV有極高的專一性（體外試驗發現entecavir對其他病毒幾乎沒有影響）。體外試驗發現它對病毒的抑制效力是Lamivudine的30倍，且對Lamivudine抗藥性病毒株也有效。 作用機制：可以抑制病毒反轉錄酵素，阻斷病毒DNA的合成而抑制病毒的複製。 副作用：極少,Method,d
12、ouble-blind trial 715 patients with HBeAg+ chronic hepatitis B who had not previously received a nucleoside analogue. 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. Test: histologic improvement. serum HBV DNA level, HBeAg loss and seroconversion, and normalization
13、of the alanine aminotransferase level.,Histologic improvement,entecavir group (72 %). lamivudine group (62 %). P = 0.009,PCR、ALT、 Serum DNA & HBeAg seroconversion,No viral resistance to entecavir was detected. Safety was similar in the two groups,Results,Results,Conclusions,Among patients with HBeAg-positive chronic hepatitis B, the rates of histologic, virologic, and biochemical improvement are significantly higher with entecavir than with lamivudine. The safety profile of the two agents is similar, and there is no evidence of viral resistance to entecavir.,The end,HBV多聚酶模型,核苷酸结合槽,
