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HBV 治疗 : 用什么开始 ?

HBV 治疗 : 用什么开始 ?. This program is supported by educational grants from. 幻灯目录. HBV 治疗目标 已经公认的 HBV 治疗 病人的入选标准 初开始治疗方案 : 干扰素和核苷类 选择核苷类 选择干扰素类 其他考虑. HBV 治疗目标，病人评估和入选. HBV 的治疗目标. HBV 感染不能完全清除达到“治愈” 治疗目标 预防或逆转因严重肝损害导致的综合症及死亡 对 IHBeAg- 阳性和 HBeAg- 阴性病人

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HBV 治疗 : 用什么开始 ?

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  1. HBV 治疗: 用什么开始? This program is supported by educational grants from

  2. 幻灯目录 • HBV治疗目标 • 已经公认的HBV治疗 • 病人的入选标准 • 初开始治疗方案: 干扰素和核苷类 • 选择核苷类 • 选择干扰素类 • 其他考虑

  3. HBV 治疗目标，病人评估和入选

  4. HBV的治疗目标 • HBV感染不能完全清除达到“治愈” • 治疗目标 • 预防或逆转因严重肝损害导致的综合症及死亡 • 对IHBeAg-阳性和HBeAg-阴性病人 • 治疗目的是降低复制使病毒量HBV DNA <10-15 IU/mL • Can allow biochemical remission and prevent further liver injury

  5. GoaHBV治疗总目标ls of HBV Therapy • In HBeAg-阳性病人positive patients (cont) • HBeAg 下降和血清逆转是治疗成功的二期表现loss and seroconversion represent a secondary form of treatment success • Associated with improved long-term outcomes • In HBsAg-阳性和阴性HBeAg-者 • HBsAg 下降和血清转阴是最大的治疗成功 • 病毒抑制的最好指标 • 长期预后良好，发展为肝硬化程度最低 • 大多数病人都达不到这个效果

  6. 随时间演变的HBV治疗 Peginterferon alfa-2a Entecavir Lamivudine Tenofovir 1990 2006 1998 2002 2005 2008 Interferon alfa-2b Telbivudine Adefovir

  7. HBeAg-阳性者推荐的启动治疗 *Persistent (> 3-6 mos). †TDF not FDA approved at time of publication. • Criteria for HBV DNA, ALT and disease stage/grade must all be met • If not, guidelines recommend monitoring and consideration of treatment based on individual’s age, health status, and stage of infection/disease 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. J Hepatology. 2009;50:227-242.

  8. HBeAg-阴性患者的启动治疗 *Persistent (> 3-6 mos). †TDF not FDA approved at time of publication. ‡ Consider liver biopsy if > 2000 IU/mL and treat if moderate/severe inflammation and/or fibrosis found. • Criteria for HBV DNA, ALT and disease stage/grade must all be met • If not, guidelines recommend monitoring and consideration of treatment based on individual’s age, health status, and stage of infection/disease 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.

  9. 某些可以考虑HBV治疗的情况 • 不管HBV DNA和ALT水平如何 • 迅速发生肝坏死的病人 • 肝硬化失代偿期 • DNA > 2,000 IU/mL, ALT水平忽略不计 • 肝硬化失代偿经病例证实 • 肝移植后HBV感染 • HBV携带者免疫抑制或cytotoxic chemotherapy Lok A, et al. Hepatology. 2007;45:507-539. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227–242. Sorrell MF, et al. Ann Intern Med. 2009;150:104-110.

  10. HBeAg状态和治疗反应关系 *After seroconversion.

  11. 一线核苷类和干扰素的选择 *Prolonged treatment not feasible. † Newer vs older nucles(t)ides.

  12. 选择一线核苷类似物

  13. 选择影响因素 • 对治疗反应好的相关因素 • 高ALT • 低 HBV DNA • 特殊病人群体 • 老年人 • 优先治疗 • HIV 合并感染 • 没有HCV合并感染

  14. 考虑选择起始药物的几个问题 安全性 疗效 (稳定性=耐药屏障)

  15. 有效性 (Potency)

  16. 治疗1年HBV DNA测不到 Not head-to-head trials; different patient populations and trial designs HBeAg 阳性 HBeAg 阴性 100 100 91 90 88 76 80 80 67 60-73 60 60 60 51-63 Undetectable* HBV DNA (%) 40-44 40 40 20 20 13-21 0 0 LAM ADV ETV LdT TDF LAM ADV ETV LdT TDF *By PCR-based assay (LLD ~ 50 IU/mL) except for some LAM studies. Lok A, et al. Hepatology. 2007;45:507-539. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242.

  17. HBeAg-阳性病人1年治疗后发生HBeAg 下降/血清逆转 Not head-to-head trials; different patient populations and trial designs HBeAg Loss HBeAg Seroconversion 100 100 80 80 60 60 HBeAg Loss/Seroconversion (%) 40 40 32 26 24 23 22 22 21 21 20 20 12-18 NR 0 0 LAM ADV ETV LdT TDF LAM ADV ETV LdT TDF 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;359:2442-2455.

  18. HBeAg-阳性病人巩固治疗 HBeAg血清逆转 Not head-to-head trials; different patient populations and trial designs 100 LAM ADV ETV LdT TDF 80 60 50 48 47 Patients (%) 40 37 40 31 29 29 27 22 23 21 21 20 12 0 1 2 3 4 5 Years of Therapy *With sustained undetectable HBV DNA. 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. 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. 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.

  19. HBeAg-阳性治疗后逐渐HBsAg 丢失 Not head-to-head trials; different patient populations and trial designs *Patients generally withdrew from therapy after HBeAg seroconversion was achieved and any patients achieving HBsAg loss after this point are not calculated 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 Viral Hep. 2009; In press.

  20. 治疗1年ALT正常，组织学表现好转 *Significant variation in the baseline HBV DNA and ALT between trials. Lai 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 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.

  21. 耐药和治疗稳定性

  22. 什么因素决定耐药率? Potency 和基因屏障 • Potency is only 1 part of the equation • 耐药相关的药物学屏障 • 剂量安全性 • 血液水平 • 组织浓度n • 耐药基因屏障 • The number of substitutions needed for primary antiviral drug resistance • Probably at least as important as potency 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. Baldick 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.

  23. 耐药率发生相关因素? Potency vs Genetic Barrier (cont) • LAM: rtM204V/I and rtA181T (also possibly V) • Compensatory mutations: rtL180M, rtV173L, and rtL80V/I • LdT: rtM204I (not rtM204V) • ADV: rtA181T and rtN236T • Combination of low genetic barrier drugs: at least 2 mutations required • ETV: at least 3 mutations required • rtL180M + rtM204V + 1 of the following: rtT184G or rtS202I or rtM250V change • TDF: no signature resistance mutations identified at 2 years 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. Baldick 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.

  24. 第一次口服核苷类患者耐药率的累积 Not head-to-head trials; different patient populations and trial designs LAM ADV ETV LdT TDF 100 80 70 67 60 49 Patients (%) 38 40 29 24 18 17 20 11 4 3 1.2 1.2 1.2 1.2 0.2 0.5 0 0 0 0 1 2 3 4 5 6 Year EASL HBV Guidelines. J Hepatol. 2009;50:227-242. Tenny DJ, et al. EASL 2009. Abstract 20.

  25. 小结药力和基因屏障对耐药的影响 • LAM and LdT • Potent agents with low genetic barriers and high rates of resistance • ADV • Less potent agent with low pharmacologic barrier with intermediate rate of resistance • ETV • Potent agent with high pharmacologic and genetic barriers and low rates of resistance • TDF • Potent agent with high pharmacologic and low rates of resistance, genetic barrier not yet defined

  26. 复合治疗

  27. 复合药物治疗组合方式? • No combination therapy has convincingly shown increased short-term efficacy in nucleos(t)ide-naive patients • LdT + LAM vs LdT vs LAM[1] • LAM + ADV vs LAM[2] • FTC + ADV vs ADV[3] • TDF + FTC vs TDF[4] • Currently available drugs have excellent resistance profile • Study to generate data sufficient for approval of frontline combination treatment unlikely to be performed • Would have to be very large, very long, require shorter-term endpoints than resistance alone, and expensive 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, et al. EASL 2009; Abstract 903.

  28. 推荐使用复合治疗的特殊病人 • 肝硬化 • 发耐药高危和肝坏死高危 • HIV/HBV 双重感染 • 选择对两中感染都有抑制作用的药物预防耐药 • 已经存在耐药 • Rates of infection with resistant virus low but increasing • 没有数据表明，选择复合治疗优于单一新药的治疗 Lok AS, et al.Hepatology.2007;45:507-539. Jacobson IM. J Hepatol. 2008;48:687-691.

  29. 小结FDA批准的口服HBV治疗 *Approximate and relative. †Number of mutations needed for primary antiviral drug resistance. ‡Only includes reported adverse events that may differ in historical incidence associated with 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 databases

  30. 初开始治疗最佳核苷类选择 • Use nucleos(t)ides as monotherapy with • Highest antiviral potency and genetic barrier to resistance • Low incidence of resistance over time • Rapid and sustained to maximize cumulative benefit • LAM/LdT/ADV not generally recommended as first-line therapy • Combination therapy may be considered in patients where avoiding resistance is especially important • Currently no data supporting this approach vs newer monotherapies • Consider individual patient characteristics in relation to safety • Comorbidities (ie, compromised renal function) • Coinfections (ie, anti-HIV activity of agents) • Conception planning 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.

  31. 小结：选择干扰素做为初始治疗

  32. 选择干扰素的相关因素 • 适合用药者 • 基因型 A or B > C or D • 基线低HBV DNA (baseline and on treatment) • 基线高ALT (baseline) • 特殊人群 • 年轻人 • 将来有生育欲望的年轻女性 • 病人自己选择 • 没有HIV合并感染 • 合并HCV感染

  33. 培干扰素治疗相关的副作用 • Patients should be carefully monitored for adverse events • Most common adverse events: flu-like symptoms (fever, chills, headache, malaise, and myalgia) as well as psychological impairment Depression Increase in Incidence/Severity Fatigue Anxiety Flu-like symptoms 0 1 2 3 4 Months Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

  34. HBeAg-阳性病人：培干扰素alfa-2a或拉米夫定或同时使用两种治疗48周比较HBeAg-阳性病人：培干扰素alfa-2a或拉米夫定或同时使用两种治疗48周比较 PegIFN 180 µg (n = 271) PegIFN + LAM (n = 271) LAM 100 mg (n = 272) 100 86 80 69 62 62 60 52 46 Patients (%) 40 39 40 30 27 27 25 24 22 20 20 0 HBeAgSeroconversion HBeAgLoss HBV DNA< 105 copies/mL (~ 20,000 IU/mL) HBV DNA< 400 copies/mL (~ 80 IU/mL) ALTNormal • HBsAg seroconversion: 0% in all 3 arms Lau GK, et al. N Engl J Med.2005;352:2682-2695.

  35. HBeAg Seroconversion After EOT (Week 48)停药后随访 100 90 Off-Treatment Follow-up (Week 72) 80 70 60 P < .001 HBeAg Seroconversion (%) 50 P = .023 40 32 27 30 19 20 10 0 PegIFN (n = 271) PegIFN + LAM (n = 271) LAM (n = 272) • HBsAg seroconversion: 3% of pegIFN groups/0% in LAM group (P = .001) Lau GK, et al. N Engl J Med.2005;352:2682-2695.

  36. HBeAg-阴性者使用培干扰素 PegIFN-2a ± 拉米夫定治疗病毒抑制情况 100 90 80 70 60 Patients with HBV DNA ≤ 400 copies/mL (%)* 50 40 30 18 17 20 13 13 10 0 1 2 3 4 Years After Therapy Completed *~ 80 IU/mL, missing data considered a nonresponse. Marcellin P, et al. AASLD 2006. Abstract. 972. Marcellin P, et al. EASL 2007. Abstract 53. Marcellin P, et al. EASL 2008. Abstract 103.

  37. HBeAg(-)患者HBsAg水平是长期耐受干扰素治疗与否的指标HBeAg(-)患者HBsAg水平是长期耐受干扰素治疗与否的指标 4-yr and 6-mo response rates higher with Wk 12 HBsAg level ≤ 1500 IU/mL vs > 1500 IU/mL in long-term cohort HBsAg ≤ 1500 IU/mL HBsAg > 1500 IU/mL 100 100 6 mos posttreatment 6 mos posttreatment 80 80 4 yrs posttreatment 4 yrs posttreatment 59 60 60 Patients With Response (%) Patients With Response (%) 39 39 34 40 40 31 23 20 20 12 9 8 7 4 2 0 0 HBV DNA ≤10,000 copies/mL HBV DNA ≤400 copies/mL HBsAg Clearance HBV DNA ≤ 10,000 copies/mL HBV DNA ≤400 copies/mL HBsAg Clearance Marcellin P, et al. AASLD 2008. Abstract 919.

  38. 早期 HBsAg 动力学反应是长期干扰素治疗成功与否的预期指标 • 治疗12周发生病毒抑制 • 对的HBsAg监测提示 • 病人可能是长期耐受者 • 病人可能成为无反应者 • 这群人需换药 Lau GK, et al. APASL 2009. Abstract PE083. Moucari R, et al. 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.

  39. 关于使用培干扰素alfa-2a作为一线治疗的小结 • 利处持久的治疗耐受，持久治疗反应，不发生耐药 • 弊处：需要粘膜下给药，很多患者发生明显毒副作用 • HBeAg 和HBsAg 血清逆转率，耐受性，和跟核苷类治疗比较等是决定治疗的因素 • HBsAg 动力学分析可以对治疗反应提供前期评估

  40. 其他跟启动治疗相关因素

  41. 对有生育欲望HBV女性治疗推荐 • 有肝损害，低病毒量 • 先怀孕，后治疗 • 中度肝损害，没有肝硬化 • 怀孕前治疗，如果起效，受孕前停止治疗 • 严重肝损害 • 孕前或孕中治疗，直到分娩前 • 轻度肝损害，高病毒量 • 在妊娠后期使用“B”类药治疗 Wedemeyer H, et al. Dtsch Med Wochenschr. 2007;132:1775-1782. EASL HBV Guidelines. J Hepatol. 2009;50:227-242.

  42. 血透和肾移植病人 • ADV and TDF have been linked to worsening renal function and should be used with caution in renally impaired patients • TDF can be used if dose adjustments are made in response to changes in glomerular filtration rates • No specific renal toxicity associated with entecavir • Dose-adaptation should be used with any agent • Should be made according to the prescribing information • Monitoring of renal function before and during therapy particularly important in patients who have multiple risk factors for renal impairment EASL HBV Guidelines. J Hepatology. 2009;50:227-242.Ha NB. AASLD 2008. Abstract 901.

  43. 小结 • 选择初始治疗方案强调高效和治疗稳定性 • 一旦 HBV复制受抑制，丢失和血清逆转表明治疗好转 • 分析治疗反应的预期因素 • 核苷类 • 选择耐药屏障最高的药物 • 合并组合治疗大多数人不适用 干扰素alfa-2a • 评估HBsAg动力学越来越重要

  44. Go Online for Additional Components of This Program! CME/CE-certified Text Module: of all the key data, plusdiscussions exploring the clinical implications CME/CE-certified Interactive Case Challenges: follow along and test your learning on cases with experts Downloadable PowerPoint slides clinicaloptions.com/HBVstart

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