HBV感染的首选治疗

1、1会计学HBV感染的首选治疗感染的首选治疗DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for

2、 therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies

3、described in these materials.Interferon alfa-2bLamivudineAdefovirPeginterferon alfa-2aTelbivudineTenofovir199019982002200520062008EntecavirAASLD 20071US Algorithm 20082EASL 20093HBV DNA, IU/mL 20,000 20,000 2,000ALT, x ULN* 2 1 1疾病的阶段和程度中-重度坏死性炎症和/或显著的纤维化 一线治疗ADV, ETV, pegIFN ETV, TDF,pegIFNETV, TDF

4、,pegIFN1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 3. EASL HBV Guidelines. J Hepatology. 2009;50:227-242. *Persistent ( 3-6 mos). TDF not FDA approved at time of publication.HBV DNA, ALT 和组织学必须全部满足条件 否则, 建议观察，根据患者年龄、健康状况和疾病的阶段给于适当的

5、治疗AASLD 20071US Algorithm 20082EASL 20093HBV DNA, IU/mL 20,000 2000 2000ALT, x ULN*1 to 2 1 1疾病的阶段和程度中-重度坏死性炎症和/或显著的纤维化 一线治疗ADV, ETV, pegIFN ETV, TDF,pegIFNETV, TDF,pegIFN*Persistent ( 3-6 mos). TDF not FDA approved at time of publication. Consider liver biopsy if 2000 IU/mL and treat if moderate/se

6、vere inflammation and/or fibrosis found.HBV DNA, ALT 和组织学必须全部满足条件 否则, 建议观察，根据患者年龄、健康状况和疾病的阶段给于适当的治疗1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 3. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242. Lok A, et al. Hepatology

7、. 2007;45:507-539. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227242. Sorrell MF, et al. Ann Intern Med. 2009;150:104-110.HBeAg 状态状态基线病毒水平基线病毒水平HBV DNA 检测不出率检测不出率抑制作用抑制作用的持续性的持续性阳性高低高*阴性低高低*血清转换后.核苷（酸）类似物核苷（酸）类似物干扰素干扰素Feature优点

8、优点缺点缺点优点优点缺点缺点给药途径口服长期/疗程不定有限疗程皮下注射抗病毒活性高低耐药率非常低无副作用非常少少见肾毒性多，不宜长期使用* HBeAg阴转和清除随治疗时间增加低高HBeAg阴转 HBV DNA抑制HBsAg阴转和清除新药较高早期事件低高(选择性病例)总体不高其它抗HIV可诱导 HIV 耐药抗HCV*Prolonged treatment not feasible. Newer vs older nucles(t)ides.效能效能(潜能潜能)耐药屏障耐药屏障 (持久性持久性)安全性安全性*By PCR-based assay (LLD 50 IU/mL) except for

9、some LAM studies.Lok A, et al. Hepatology. 2007;45:507-539. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242.Not head-to-head trials; different patient populations and trial designsHBeAg PositiveHBeAg NegativeUndetectable* HBV DNA (%)100806040200LAMADVETVLdTTDF40-4413-2167607660-7351-6390

10、8891100806040200LAMADVETVLdTTDFHBeAg Loss/Seroconversion (%)Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2003;348:808-816 Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Lai CL, et al. N Engl J Med. 2007;357:2576-2588. Marcellin P, et al. N Engl J Med. 2008;3

11、59:2442-2455.Not head-to-head trials; different patient populations and trial designsHBeAg 转转阴阴HBeAg 转换转换100806040200LAMADVETVLdTTDF322422262212-18212321100806040200LAMADVETVLdTTDFNRYears of TherapyPatients (%)*With sustained undetectable HBV DNA.Chang TT, et al. N Engl J Med. 2006;354:1001-1010. La

12、i CL, et al. N Engl J Med. 2007;357:2576-2588. Marcellin P, et al.N Engl J Med. 2003;348:808-816. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Lok AS, et al. Gastroenterology. 2003;125:1714-1722. Leung NW, et al. Hepatology. 2001;33:1527-1532. Dienstag JL, et al. Hepatology. 2003;37:748-755

13、. Marcellin P, et al. Hepatology. 2008;48:750-758. Liaw YF, et al. Gastroenterology. 2009;136:486-495. Gane E, et al. AASLD 2008. Abstract 729. Heathcote E, et al. AASLD 2008. Abstract 158.Not head-to-head trials; different patient populations and trial designs1008060402001234522122123 2129312927403

14、7475048LAMADVETVLdTTDFNot head-to-head trials; different patient populations and trial designsYear12345LAM1- 1ADV0-55ETV25NANANALdT0-NANANATDF36NANANA*Patients generally withdrew from therapy after HBeAg seroconversion was achieved and any patients achieving HBsAg loss after this point are not calcu

15、lated in rates. Median follow-up 80 weeks.Gish RG, et al. Gastroenterology. 2007;133:1437-1444. Heathcote E, et al. AASLD 2008. Abstract 158. Hsu, et al. EASL 2009. Abstract 911. Hadziyannis SJ, et al. Gastroenterology. 2006;131:1743-1751. Yao GB, et al. J Dig Dis. 2009;10:131-137. Gish RG, et al. J

16、 Viral Hep. 2009; In press.HBeAg PositiveOutcome, %LAMADVETVLdTTDFALT复常41-7548687769组织学改善49-5653726574HBeAg NegativeOutcome, %LAMADVETVLdTTDFALT复常60-7972787477组织学改善60-6664706772Lai CL, et al. N Engl J Med. 1998;339:61-68. Dienstag JL, et al. N Engl J Med. 1999;341:1256-1263. Lau GK, et al. N Engl J

17、Med. 2005;352:2682-2695. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Lai CL, et al. N Engl J Med. 2007;357:2576-2588. Marcellin P, et al. N Engl J Med. 2003;348:808-816. Marcellin P, et al. 2008;359:2442-2455.*Significant variation in the baseline HBV DNA and ALT between trials.Allen MI, et a

18、l. Hepatology. 1998;27:1670-1677. Yatsuji H, et al. Antimicrob Agents Chemother. 2006;50: 3867-3874. Qi X, et al. Antivir Ther. 2007;12:355-362. Villeneuve JP, et al. J Hepatol. 2003;39:1085-1089. Baldick CJ, et al. Hepatology. 2008;47:1473-1482. Seifer M, et al. Antiviral Res. 2009;81:147-155. Heat

19、hcote E, et al. AASLD 2008. Abstract 158. Marcellin P, et al. AASLD 2008. Abstract 146. Allen MI, et al. Hepatology. 1998;27:1670-1677. Yatsuji H, et al. Antimicrob Agents Chemother. 2006;50: 3867-3874. Qi X, et al. Antivir Ther. 2007;12:355-362. Villeneuve JP, et al. J Hepatol. 2003;39:1085-1089. B

20、aldick CJ, et al. Hepatology. 2008;47:1473-1482. Seifer M, et al. Antiviral Res. 2009;81:147-155. Heathcote E, et al. AASLD 2008. Abstract 158. Marcellin P, et al. AASLD 2008. Abstract 146. Not head-to-head trials; different patient populations and trial designsEASL HBV Guidelines. J Hepatol. 2009;5

21、0:227-242. Tenny DJ, et al. EASL 2009. Abstract 20. Year0244967703812345Patients (%)80406020100031118290.2 1.21.24 00171.261.2LAMADVETVLdTTDF0.5？1. Lai CL, et al. Gastroenterol. 2005;129:528-536. 2. Sung JJ, et al. J Hepatol. 2008;48:728-735. 3. Hui CK, et al. J Hepatol. 2008;48:714-720. 4. Berg T,

22、et al. EASL 2009; Abstract 903.Lok AS, et al. Hepatology. 2007;45:507-539. Jacobson IM. J Hepatol. 2008;48:687-691. *Approximate and relative. Number of mutations needed for primary antiviral drug resistance.Only includes reported adverse events that may differ in historical incidence associated wit

23、h LAM and, therefore, potentially affecting selection vs other agents. Pancreatitis has been reported as a class effect and all agents have to be dose adjusted for renal insufficiency. From HIV databasesOral Drug效能效能*药物屏障药物屏障基因屏障基因屏障副作用副作用LAM+1-ADV+1肾毒性 (1% per year)ETV+3-LdT+1肌痛, 神经病, 心律失常 (罕见)TDF+

24、?肾毒性Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. EASL HBV Guidelines. J Hepatol. 2009;50:227-242. Lok AS, et al. Hepatology. 2007;45:507-539.Months抑郁疲乏流感样症状焦虑焦虑12340Increase in Incidence/SeverityKeeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 020406080100PegIFN 180

25、 g (n = 271)PegIFN + LAM (n = 271)LAM 100 mg (n = 272)272420HBV DNA 105 copies/mL( 20,000 IU/mL)ALTNormalHBeAgLossHBeAgSeroconversion302722528662394662Patients (%)HBsAg seroconversion: 0% in all 3 armsHBV DNA 400 copies/mL( 80 IU/mL)256940Lau GK, et al. N Engl J Med. 2005;352:2682-2695.Lau GK, et al

26、. N Engl J Med. 2005;352:2682-2695.HBeAg Seroconversion (%)32271901020304050PegIFN(n = 271)PegIFN + LAM(n = 271)LAM(n = 272)P .001P = .023HBsAg seroconversion: 3% of pegIFN groups/0% in LAM group (P = .001)60708090100Off-Treatment Follow-up (Week 72)Marcellin P, et al. AASLD 2006. Abstract. 972. Mar

27、cellin P, et al. EASL 2007. Abstract 53. Marcellin P, et al. EASL 2008. Abstract 103. * 80 IU/mL, missing data considered a nonresponse.Years After Therapy CompletedPatients with HBV DNA 400 copies/mL (%)*1009080706050403020100123413131817Lau GK, et al. APASL 2009. Abstract PE083. Moucari R, et al.

28、Hepatology. 2009;49:1151-1157. Brunetto MR, et al. Hepatology. 2009;49:1411-1150. Moucari R, et al. J Hepatol. 2009;50:1084-1092. Perillo RP. Hepatology. 2009;49:1063-1065.Wedemeyer H, et al. Dtsch Med Wochenschr. 2007;132:1775-1782.EASL HBV Guidelines. J Hepatol. 2009;50:227-242. EASL HBV Guideline

29、s. J Hepatology. 2009;50:227-242. Ha NB. AASLD 2008. Abstract 901.nDisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and