HBV 治疗 : 用什么开始 ?

HBV 治疗 : 用什么开始 ?

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HBV Treatment: What to Start?

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

– 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



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



Interferon alfa-2b

Lamivudine

Adefovir

Peginterferon alfa-2a

Telbivudine

Tenofovir

1990 1998 2002 2005 2006 2008

Entecavir

随时间演变的 HBV 治疗



HBeAg- 阳性者推荐的启动治疗

AASLD 2007[1] US Algorithm 2008[2] EASL 2009[3]

HBV DNA, IU/mL > 20,000 > 20,000 ≥ 2,000

ALT, x ULN* > 2 > 1 > 1

疾病程度 Moderate/severe necroinflammation and/or significant fibrosis

一线方案 ADV,† ETV, pegIFN

ETV, TDF,pegIFN

ETV, TDF,pegIFN

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.

*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



HBeAg- 阴性患者的启动治疗

AASLD 2007[1] US Algorithm 2008[2] EASL 2009[3]

HBV DNA, IU/mL > 20,000‡ > 2000 ≥ 2000

ALT, x ULN* 1 to > 2 > 1 > 1

疾病程度 Moderate/severe necroinflammation and/or significant fibrosis

一线治疗 ADV,† ETV, pegIFN

ETV, TDF,pegIFN

ETV, 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/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.



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.



HBeAg 状态和治疗反应关系

HBeAg 状态基线病毒量 HBV DNA 测不到病毒抑制持久性阳性 Higher 高 Less 少 Higher* 高阴性 Lower 低 More 多低 Lower

*After seroconversion.



一线核苷类和干扰素的选择Nucleos(t)ides Interferon-Based Therapy

Feature Pro Con Pro Con

Administration OralLong term/ indefinite

Finite duration Subcutaneous

Antiviral activity HighLow durable rates DNA suppression

ResistanceVery low

resistance† No

Adverse events MinimalRare renal tox with nucleotide

Substantial*

HBeAg loss and clearance

HBeAg loss over time

Lower rates vs IFN

Higher rates vs nucles(t)ides

HBeAg loss ≠ HBV DNA suppression

HBsAg loss and clearance

Higher and earlier events† Low rates

High rates (select populations)

Low rates in general patient groups

Other Anti HIV (TDF)May induce HIV

resistance (TDF/ETV)

Anti HCV/HDV

*Prolonged treatment not feasible. † Newer vs older nucles(t)ides.



选择一线核苷类似物



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



疗效

( 稳定性 =耐药屏障 )

考虑选择起始药物的几个问题

安全性



有效性 (Potency)



治疗 1 年 HBV DNA 测不到

*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.

Not head-to-head trials; different patient populations and trial designs

HBeAg 阳性 HBeAg 阴性

Un

det

ecta

ble

* H

BV

DN

A (

%) 100

80

60

40

20

0LAM ADV ETV LdT TDF

40-44

13-21

6760

76

60-73

51-63

90 88 91100

80

60

40

20




HBeAg- 阳性病人 1 年治疗后发生 HBeAg 下降 / 血清逆转

HB

eAg

Lo

ss/S

ero

con

vers

ion

(%

)

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.


HBeAg Loss HBeAg Seroconversion100

80

60

40

20


3224 22 26

2212-18

21 23 21

100

80

60

40

20


NR



Years of Therapy

Pat

ien

ts (

%)

HBeAg- 阳性病人巩固治疗 HBeAg 血清逆转

*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.

Not head-to-head trials; different patient populations and trial designs100

80

60

40

20

01 2 3 4 5

22

122123 21

29 31 29 27

40 3747 50 48

LAM ADV ETV LdT TDF



HBeAg- 阳性治疗后逐渐 HBsAg 丢失


Year 1 2 3 4 5

LAM 1 -- -- -- < 1

ADV 0 -- -- 5 5

ETV 2 5† NA NA NA

LdT 0 -- 5.6 NA NA

TDF 3 6 NA NA NA

*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.

*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.



治疗 1 年 ALT 正常，组织学表现好转

HBeAg Positive

Outcome, % LAM ADV ETV LdT TDF

Normalization of ALT 41-75 48 68 77 69

Histologic improvement 49-56 53 72 65 74

HBeAg Negative

Outcome, % LAM ADV ETV LdT TDF

Normalization of ALT 60-79 72 78 74 77

Histologic improvement 60-66 64 70 67 72

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.

*Significant variation in the baseline HBV DNA and ALT between trials.*Significant variation in the baseline HBV DNA and ALT between trials.



耐药和治疗稳定性



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.



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 yearsAllen 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.



第一次口服核苷类患者耐药率的累积


EASL HBV Guidelines. J Hepatol. 2009;50:227-242. Tenny DJ, et al. EASL 2009. Abstract 20.

Year

0

24

49

67 70

38

1 2 3 4 5

Pat

ien

ts (

%)

80

40

60

20

100

03

1118

29

0.2 1.2 1.24

00

17

1.2

6

1.2

LAM ADV ETV LdT TDF

0.5



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



复合治疗



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.



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.



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

Oral Drug

Antiviral Potency*

Pharmacologic Barrier

Genetic Barrier†

Adverse Events‡

LAM + + 1 --

ADV ++ + 1 Nephrotoxicity (≤1% per year)

ETV ++++ ++++ 3 --

LdT ++ ++ 1 Myalgia, myositis, neuropathy,

cardiac arrhythmia (rare)

TDF ++++ ++++ ? Nephrotoxicity§



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.



小结：选择干扰素做为初始治疗



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



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

Months

Depression

Fatigue

Flu-like symptoms

Anxiety

1 2 3 40

Incr

ease

in

In

cid

ence

/Sev

erit

y

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.



0

20

40

60

80

100

PegIFN 180 µg (n = 271) PegIFN + LAM (n = 271) LAM 100 mg (n = 272)

27 24 20

HBV DNA< 105 copies/mL(~ 20,000 IU/mL)

ALTNormal

HBeAgLoss

HBeAgSeroconversion

30 27 22

52

86

62

3946

62

Pat

ien

ts (

%)

HBsAg seroconversion: 0% in all 3 arms

HBV DNA< 400 copies/mL

(~ 80 IU/mL)

25

69

40

Lau GK, et al. N Engl J Med. 2005;352:2682-2695.

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



Lau GK, et al. N Engl J Med. 2005;352:2682-2695.

HB

eAg

Ser

oco

nve

rsio

n (

%)

3227

19

0

10

20

30

4050

PegIFN(n = 271)

PegIFN + LAM(n = 271)

LAM(n = 272)

P < .001

P = .023

HBsAg seroconversion: 3% of pegIFN groups/0% in LAM group (P = .001) HBsAg seroconversion: 3% of pegIFN groups/0% in LAM group (P = .001)

60

70

80

90100

Off-Treatment Follow-up (Week 72)

HBeAg Seroconversion After EOT (Week 48) 停药后随访



HBeAg- 阴性者使用培干扰素 PegIFN-2a ± 拉米夫定治疗病毒抑制情况

Marcellin P, et al. AASLD 2006. Abstract. 972. Marcellin 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 Completed

Pat

ien

ts w

ith

HB

V D

NA

≤

400

cop

ies/

mL

(%

)*

100908070605040302010

01 2 3 4

13 13 18 17



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

Marcellin P, et al. AASLD 2008. Abstract 919.

6 mos posttreatment4 yrs posttreatment

HBsAg ≤ 1500 IU/mL

HBV DNA ≤10,000

copies/mL

HBV DNA ≤400

copies/mL

HBsAg Clearance

Pat

ien

ts W

ith

R

esp

on

se (

%)

59

39 3931

7

23

60

40

20

0

6 mos posttreatment4 yrs posttreatment

HBsAg > 1500 IU/mL

HBV DNA ≤ 10,000

copies/mL

HBV DNA ≤400

copies/mL

HBsAg Clearance

Pat

ien

ts W

ith

R

esp

on

se (

%)

34

12 9 82 4

60

40

20

0

100

80

100

80



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.

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.



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



其他跟启动治疗相关因素



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.



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.



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

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HBV 治疗 : 用什么开始 ?

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