A Comparison of Entecavir and Lamivudine for HBeAg-Positive Chronic Hepatitis B

1. A Comparison of Entecavir and Lamivudinefor HBeAg-Positive Chronic Hepatitis B 報告人：朱郁芬

2. 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

3. Hepatitis B virus Virology Large surfaceantigen （HBsAg） Middle surfaceantigen （HBsAg） Genomic DNA Nucleocapsid （HBcAg） DNA polymerase Envelope （HBsAg） RNA primer Small surfaceantigen （HBsAg）

4. Replication cycle for HBV Infectious HBV virion Infectious HBV virion HBsAg envelopes DNA pol RT Partially double-stranded DNA (-)-DNA Encapsidated pregenomic mRNA A(n) cccDNA mRNA

5. How HBV cause disease

6. Hepatitis B Progression Acute HBV infection 90% neonates 25–30% children <10% adults ~2% Chronic infection 15–40% Fulminant hepatic failure Progressive chronic hepatitis Inactivecarrier state Cirrhosis Decompensated cirrhosis Death HCC EASL Consensus Guidelines. J Hepatol 2003; Lok, McMahon. Hepatology 2004 (AASLD Guidelines)

7. Immune Immune Low replicative Reactivation tolerance clearance phase phase HBeAg -ve/ anti-HBe +ve HBeAg +ve > < < > >105 cp/mL HBV-DNA <105 cp/mL 109–1010 cp/mL 107–108 cp/mL ALT Normal/ mild CH Moderate/severe CH Normal/mild CH Moderate/severe CH Cirrhosis Inactive cirrhosis Cirrhosis HBeAg +ve Chronic hepatitis Inactive-carrier state HBeAg -ve Chronic hepatitis Stages of Chronic HBV Infection Adapted from Fattovich. Sem Liver Dis 2003

8. 2 billion with evidence of 25% die of cirrhosis or liver cancer HBV infection 300–400 million with World population chronic HBV 6 billion The Global Disease • Half of the world’s population lives in an area with high HBV prevalence WHO and CDC fact sheets, available at www.who.int and www.cdc.gov

9. Prevalence of chronic HBV carriers in different countries HBsAg Endemicity 8% and above – High 2% - 8% - Intermediate Below 2% - Low From: World Health Organization. Introduction of hepatitis B vaccine into childhood immunization services, 2001, Geneva, WHO, WHO/v&B/01.31

10. Treatment：Entecavir ＆ Lamivudine

11. HBV study important record • 1965find virus antigen • 1970 find virus particle • 1973 find polymerase in virus particle • 1974 atomic structure for restriction enzyme • 1976 treat for IFN-α • 1977 find -antigen in liver cell • 1982 know HBV replication • 1986 reassembled HBV vaccine • 1993 Lamivudine clinical try • 1999 Lamivudine Approvable • 2002 PEG - clinical try • 2005 Entecavir Approvable

12. New Approval Medicine • Interferon • Intron A： recombinant interferon α-2b ；made by Schering-Plough • Nucleotide analogue • Lamivudine ；made by GlaxoSmithKline • Entecavir； made by Bristol-Myers Squibb • Adefovir dipivoxil；made by Gilead Sciences

13. 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，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（ALT≧5X）。 • 無肝功能代償不全。

14. Interferon signal transduction

15. 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面的問題

16. 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（ALT≧5X），或已發生肝代償不全者（有黃膽且凝血酶原時間超過三秒）。

17. Replication cycle for HBV Lamivudine Infectious HBV virion Infectious HBV virion HBsAg envelopes DNA pol RT Partially double-stranded DNA (-)-DNA Encapsidated pregenomic mRNA A(n) cccDNA mRNA

18. 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

19. Method • double-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 of the alanine aminotransferase level.

20. Histologic improvement • entecavir group (72 %). • lamivudine group (62 %). • P = 0.009

21. PCR、ALT、 Serum DNA &HBeAg seroconversion • No viral resistance to entecavir was detected. • Safety was similar in the two groups

22. Results

23. Results

24. 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.

25. The end

28. HBV多聚酶模型 核苷酸结合槽