Fattovich G et al. Hepatology 1995; Liaw YF et al. Liver 1989; Ikeda K et al. J Hepatol 1998.

1
??????????????

• ????
• ??? ??

2
????????????
3
??????????(5??????????)
????
??????
12-20
???
?????
20-23
6-15
45
??????
???????
86
Fattovich G et al. Hepatology 1995 Liaw YF
et al. Liver 1989Ikeda K et al. J Hepatol 1998.
??
4
???HBV????????????????
5
??HBV DNA????????????
?26?????????
12
5
10
4
3
8
??????(HAI)
2
6
HAI???????
1
4
0
2
1
2
3
4
5
1
0
2
0
2
4
6
8
10
12
log10 HBV DNA ??????
?? HBV DNA ??, log10 copies/mL
????????????, HAI? HBV DNA??????
(r0.96 Plt3x10-6)
???????????,HAI?HBV DNA???? (r0.78 P0.0001)
Mommeja-Marin H, et al. Hepatology.
2003371309-1319.
6
HBV??????????(??????3851?HBsAg????13???)
??HBV DNA?? ????? ????? ??????
????????(95CI) ??HBeAg(-)?? ?103 ??/ml
24873.5 2132 104
1.0 104 ??/ml
7123.3 631
55 1.9 (1.4-2.7)
?105??/ml 4663.4 451
96 4.9
(3.7-6.4) ??HBeAg()?? ?103 ??/ml
230.7 22 2
2.6(0.6 -10.5) 104
??/ml 191.3 18
3
6.2(1.9 -19.5 ?105??/ml 5332.8
520 135
8.6(6.6 -11.2)
????????-HCV???????????? Plt0.01, Plt0.0O1




Chen CJ et al. J Hepatol
2005,42172 (A476)
7
HBVDNA?????????(??????3851?HBsAg????13???)
??HBV DNA??
test of trend plt0.01


Chen CJ. J Hepatol 2005,4216(A35)
8
???????HCC??????????

• Chen et al, 2004 ????HBV????????????????????
• ????10?
• HBsAg???????????
• ????? 83,794?,???19921993?
• 12-15 ?HBsAg??
• ?????HBsAg??????????????????

Chen, et al. J Gastroenterol Hepatol.
200419(Suppl.)A245.
9
HCC ??????HBV???????
1.00
HBV DNA (-)
0.96
???HBV DNA 1.6 x 103 - lt 105 cp/mL RR 1.8
(0.5-5.8)
0.92
??????
0.88
???HBV DNA gt 105 cp/mL RR 9.9 (3.2-31.0)
0.84
0.80
0
1
2
3
4
5
6
7
8
9
10
11
12
???? (?)
Chen G et al. 55th AASLD, 2004. Abstract 1362
10
??????????HBV???????
Chen G et al. 55th AASLD, 2004. Abstract 1362
11
???????????????
??11 893?????????????????
12
HBsAg(), HBeAg()
RR 60.2
10
8
?????()
6
RR 9.6
4
HBsAg(), HBeAg(-)
2
HBsAg(-), HBeAg(-)
0
??
0 1 2 3 4 5 6 7
8 9
Yang HI, et al. N Engl J Med, 2002
12
??????????????!
???? HBV ??
13
????

• ???????????????????????????????????/????????,????1
  
• ????????????????2
• ????????????HBV,??????????????,??????,????????????
  ???HCC????????,???????????????3
• ?????????????,?????????????4

1. APASL Guideline 2005, 2. AASLD Guideline 2004,
3. ??????????2005, 4. A Treatment Algorithm for
the Management of CHB Virus Infection in the US
14
??????????
HBeAg HBV DNA (copies/mL) ALT ??
lt 105 ??
105 2?ULN ????? ???????,????
105 gt2?ULN ??
- lt 104 ??
- 104 2?ULN ????????????,????
- 104 gt2?ULN ??
Keeffe et al. Clin Gastroenterol Hepatol.
2004287-106.
15
?????????? ?????
?????
HBV DNA (copies/mL) ??
lt 104 ?????
104 ??
?????
HBV DNA ??
?????? ?? ?????
?? ??????????????
Keeffe et al. Clin Gastroenterol Hepatol.
2004287-106.
16
??CHB????
??????
??????? ??????????
?????
HBeAg??
HBeAg??
??
ALT2ULN HBV DNA1105 ??/ml
ALTlt2ULN
ALT2ULN HBV DNA1104 ??/ml
??
??
??,ALT?? ??????? ??????? ?????
17
????????

• HBeAg????????
• ??HBV DNA??,ALT??,HBeAg????
• HBeAg????????
• ?????????
• HBsAg?????
• ?????HBV DNA??,ALT???

???????(?1?)??????????
18
???????????????- HBeAg????
???
???
PEG-IFN-a2a
???
HBeAg ???? EOT 27 EOF 32
-1.95
-2.61
HBV DNA?? (log10 ??/mL)
-2.39
PEG-IFN-a2a
????
-4.48
HBeAg ???? EOT 24 EOF 27
-5.81
-7.18
????
HBeAg ???? EOT 20 EOF 19
????????????????log10
Lau et al AASLD 2004
19
????????????????????HBeAg????
???? HBeAg ??? ??
??IFN 33 Lok McMahon, 2004
Peg IFN a-2b 29 Janssen et al, 2005
Peg IFN a-2a 30 Lau et al, 2004
20
??????????????????????HBeAg????
?????????,??????? (????,??????)
17(32)
35
30
21(26)
14(23)
25
21(22)
20
HBeAg ???? (??),
15
10
5
0
-5
LdT
-10
LAM
ETV
ADV 10
Lau et al. N Engl J Med. 20053522682-2695.
Dienstag et al. N Engl J Med. 19993411256-1263.
Marcellin et al. EASL 2005. Abstract 73. Lai et
al. AASLD 2005. Abstract LB01. Chang et al.
AASLD 2004. Abstract 70.
21
???????????????- HBeAg????
HBV DNA?? (log10 ??/mL)
????(?)
Marcellin et al, EASL 2004
22
???HBeAg?????????????
HBeAg????
??????? ????? 1? ??? 6??-1?
20-30
70-80
HBeAg????
??HBeAg????
80????
20??
80 HBeAg?????????????????
??20 HBeAg????????????????????
23
HBeAg??????????????
HBeAg????
??????? ????? 1? ??? 6??-1?
2-3
HBsAg????
?????????????
??2-3 HBeAg????????????????????
24
88????????????????
?12?????????
40HBeAg ????
60HBeAg????
88???????????
25
??????????

• ???????????????,1??2?????
• ????????,??????????????????????(??????17-18??)
• ??????????????????????????????????,?????????2??3?
  ???,??????????

26
(No Transcript)
27
????????????????
100
????2 (M204V/I)
?????1,3 (N236T/A181V)
AASLD ?????
80
70
60
53
??,
42
40
29
24
18
20
11
2
0
0
2?
3?
4?
5?
1?
???????5????
1. Qi et al. EASL 2004. Abstract 57. 2. Lai et
al. Clin Infect Dis. 200336687. 3. Hadziyannis
et al. AASLD 2005. Abstract 72492
28
??????????????

• ?????????1,2
• ???????????????????96??,???????
• ??????????ETV??48??,7?????ETV??
• ?????????(Emtricitabine)3
• ??????,??????????????????????????
• ?????????4
• ??????M204I??????????????

1. Colonno et al. EASL 2005. Abstract 478. 2.
Gish et al. AASLD 2005. 3. Qi et al. EASL 2005.
Abstract 57. 4. Lai et al. Gastroenterology
2005129528-536.
29
??????????????

• ???????????
• ????????,????????
• ??????????
• ???????
• ????
• ????????

30
??

• ???????????????????????
• ??????????????????,??????
• ?????????????,????????????????????? ,???????????
• ??????????????,???????
• ????HBeAg?????????
• ????????????
• ???????????????????
• ????????????????????

31
The End Thanks
32
?????????????

• ADV 438 5???

GSK International Dr. Jon Dixon
33
?????HBeAg???????? 240 ?
????? ?5?
????? ?4?
0
48?
96?
144?
240?
??? (4???????????????)
???
??? (4??????????????????)
???
???
???10 mg/??????48???21?????????
???????????? ????????
Hadziyannis et al. AASLD 2005
34
????
???? 4????? (n55) 5????? (n70)
?? () 84 81
??? () 69 70
???? () 29 26
????? (?) 46 47
ALT??? (U/L) 62 99
HBV DNA??? (log copies/mL) 5.85 7.08
35
???? ???
???? 4????? (n55) 5????? (n70)
???????????? 22 24
Knodell ????????? 8.0 8.5
Ishak ???????? 2.5 2.0
????????? 5 7
36
??? HBeAg??????4?????HBV DNA lt1000??/mL?ALT???(
Kaplan Meier????)
?? ()
N 79 79
70 69
Hadzyannis SJ et al J Hepatol
(Abst) 2005
37
??? HBeAg??????5?????(??????????)
??HBV DNA lt 1000 ??/mL
ALT ???
100
?? ()
78
80
77
75
75
72
71
69
68
67
67
60
40
20
0
48
96
144
192
48
96
144
192
240
240
???? (?)
n 69 58 69 65 55 64
53 64 59 55
Hadziyannis et al. EASL 2005, Hadziyannis et
al. AASLD 2005
38
?????HBeAg??????96?Knodell?????
2
1
48?
0
48?
48?
96?
96?
96?
-1
Knodell ????
-2
-3
0
-4
-5
??? ? ???
???????
???? ???
N20 N20 N19 N19
N8 N8
Hadziyannis SJ et al, NEJM 2005
39
?????4???5?????????????

• ??5????50?????????????????

?? ()
??
???
??
4? (n 22)
5? (n 24)
4? (n 22)
5? (n 24)
????
??????
?????4??5?Knodell?????????????????4.5??5?
Ishak????????????????1?.
Hadziyannis et al. AASLD 2005
40
?????4???5???Ishak?????
Ishak??????? 1??????
80
17/24 (71)
?? ()
P .005
60
12/22 (55)
40
20
0
0
1
2
3
4
5
???????
???5????????Cochran-Armitage????
1?????????????.
Hadziyannis et al. AASLD 2005
41
?????HBeAg??????5?????

• 22 ?(18)?????????????????
• ????5??,??1????? lt2.0mg/dL ,4 ??????????????
  0.5mg/dL

42
?????????????????????
100
??? ()
????
80
?????
70
70
53
60
42
40
29
24
18
20
11
2
0
0
1
2
3
4
5
????
1. Lai et al. Clin Infect Dis. 200336687-96 2.
Colonno et al. Hepatology 200440 661A. 3. Xiong
et al. EASL 2005. 4. Gish et al. AASLD 2005.
Abstract 67146. 5. Sherman et al. AASLD 2004
43
??48??, 30??????? gt 1000 ??/mL
????????????????
????1?? HBV DNA?????3???????????
??30(34?)???, 10?(29) ?144??????????
24 (70.6) ????????
30 HBV DNAgt 3 log10
30 HBV DNAgt 3 log10
70 HBV DNAlt 3 log10
70 HBV DNAlt 3 log10
10 (29.4) ?144??????
4 (5.0) ?144??????
76 (95.0) ????????
Locarnini et al. EASL 2005. Abstract 36.
44
???HBeAg????????5????
???? ?5???? ?5????
HBV DNA lt103 ??/ml 37/55 67
ALT ?? 38/55 69
Ishak??????? (?? 1? ) 17/24 71
A181V ?/? N236T ?? 29
?????????0.5mg/dL 4/55 3
Hadziyannis et al AASLD 2005
45
? ?

• HBeAg???????????????????????????????
• ??????????
• ALT?????
• HBV DNA????
• ?????
• ?????5??????????29

46
???????????HBeAg??????

• 64 ?HBeAg??, ????????????
• ?????3??

20???????,???????
44???????
Manolakopoulos et al AASLD 2005
47
???????????HBeAg??????
6m
12m
24m
HBV DNA ?????? (log copies/ml)
3.17
3.32
3.29
3.41
3.39
4.34
Manolakopoulos et al AASLD 2005
48
??????????????????????

• ??
• ???????50?????
• 47???YMDD??
• 3?rtA181T??
• 48?
• 9/47 (19) ??????????
• 1 A181V
• 2 A181T
• 3 N236T
• 1 A181V N236T
• 2 A181T N236T

Lee et al AASLD 2005
49
???????????????????

• 8?????????????????????????? (4?????, 3??????1??,
  1??????7??),???????????
• N236T (n2), A181V (n5), A181T (n1)
• ?????????????13-19??,1?????41?????? (??????7??)
• HBV DNA ??5 log10 copies/mL
• 2???????????,1?????
• ????? (n2),????(n2), ????(n2),
  ????????(n1), ???(n1)?????????
• 3???HBV DNA??3 log10 copies/mL

Fung et al J Hepatol 2005
50
???????????????

• ?? ??50?,??????????????????,?????????????
• ?? ????4???
• ???
• ????????
• ?????????
• ????????????????????
• ????????????

Kanwal F et al, AASLD 2005
51
???????????????

• ?????
• ???? 158
• ????? 528
• ???? 720
• ????????????????????????20,011
• ??????????,?????????????????????????????????????1
  07,165
• ????????22,?????????????

Kanwal F et al, AASLD 2005
52
HBeAg????????????????????3?????????

• ?? ?????????????????????????????????
• ???????? (??) ????, ???, ??????????????????HBV??
  ????

Buti et al, AASLD 2005
53
HBeAg????????????????????3?????????
???? ?????
3??????(??) 10,125 22,141
3??????? 30.6 77.0
????-??(3?????????????????) 33,121 28,745
Buti et al, AASLD 2005
54
HBeAg????????????????????3?????????

• ???????3????????????2.2?
• ??????????????????????2.5?
• ??,????????????????????????????????

Buti et al, AASLD 2005
55
ADF 30001 Study?????????????????????(ADV)????HB
eAg???????? ??????????????????II/III?????????

• ???????
• ??????????
• ??? ??

56
????
57
??????

• HBVDNA
• 104????????HBVDNA????????
• 104????HBV DNA??(lt300??/??)?????
• 104???????, HBVDNA????????(???HBVDNA?????105??/ml
  ???2log10,??COBAS AMPLICORTM HBV
  MONITOR,?????lt300??/??)
• ALT
• 104????????ALT?????
• HBeAg/ HBeAb
• 104??HBeAg???????
• 104??HBeAg????(???/???)????
• ????104???,????HBeAg?????????

58
?????

• ???????? 480
• ?????????? 474/480(98.7)
• 6???????
• ?????????? 456/474(96.2)
• 18???????,??3????????? ,13? ????(??10???????????
  ??56???),2????

59
????-HBV DNA??
-0.2log10
-4.7log10
-4.5log10
-5.0log10
-5.0log10
-5.3log10
60
????-HBV DNA???
45
42
41
30
28
1
61
????-HBV DNA????????
94
91
89
62
????-ALT?????
78
79
76
71
69
21
63
????-HBeAg??
64
????-????(???)
65
????-????(???)
66
????-??HBeAg????

• ????????,??50???????HBeAg????,??PAA?,AAA??AAP????1
  4(17/120), 7(17/240)?13(16/120)?

??HBeAg????????????3????????HBeAg????(???HBeAg??
??-HBe???HBVDNA?105???/mL),????????3??,?HBeAg?????
?6?????????HBeAg????????????ADV,??????????????
67
????? 52-104???????????(??????)
N () PAA N120 AAA N240 AAP N120
????1????????????? 0 7 (3) 1(lt1)
??
??? 0 2(lt1) 0
?????
ALT ?? 0 0 1(lt1)1
AST ?? 0 0 1(lt1)1
????? 0 0 1(lt1)1
CPK ?? 0 2(lt1) 0
??/??????
?? 0 3(1.3) 0
?? 0 1(lt1) 0
1 ??????, ??442
68
????? 52-104???????????(??????)
??? ??? SAE ?? ???? ???? ???? ??
PAA? 71 ???? ?? ? 430 ? ??
PAA? 338 ?? ?? ? 455 ? ??
AAA? 178 ??? ?? ? 645 ? ??
AAA? 159 ???? ?? ? 728 ? ???
AAA? 411 ???? ?? ? 563 ? ??
AAA? 196 ???? ?? ? 444 ? ??
AAA? 135 ??? ?? ? 760 ? ??
AAP? 387 ?? ?? ? 560 ? ??
??????????,????? ????????
69
?????-?????

• 0.4(2/474)????????????
• PAA?1?????????
• AAA?1???????????
• ?52-104??????2???????
• 420?????????,????????
• 258???????,?????????

70
?????-?????

• ????????????3/4??????????ALT??,????????8.2(39/474
  )?
• 3??4????ALT????????????????6(27/474)?3(12/474)?
• ??????,3/4????ALT???PAA?AAA?AAP????????4(5/119)?4
  (9/236)?21(25/119)
• AAP???3/4????ALT????????,???84(21/25)????56?,19??
  ???????(68?)?ALT?????

71
?????????? -????????????????????
(??????)
N () PAA N119 AAA N236 AAP N119
??????????????? ?????? 14 (12) 26 (11) 10 (8)
???????? gt0.5mg/dL ?????? 2 (2) 0 4 (2) 0 2 (2) 0
?? 1.4 ?lt2.2 mg/dL ?????? 11 (9) 1(lt1) 22(9) 3(lt1) 8 (7) 1(lt1)
?? lt 1.4 mg/dL ?????? 1(lt1) 0 0 0 1(lt1) 0
????????????,???????????????? ????????????,???????????????? ????????????,????????????????  
72
???????? ?????YMDD???? -?????????52-104?log10
HBV DNA????(??????)
PAA N119 PAA N119 AAA N236 AAA N236 AAP N119 AAP N119
YMDDv ?YMDDv YMDDv ?YMDDv YMDDv ?YMDDv
?? HBV DNA ??? 8.7 8.6 8.7 8.8 8.9 8.8
52 ? HBV DNA????? -4.8 -5.0 -4.1 -4.6 -0.2 -0.3
104 ? HBV DNA????? -4.8 -5.3 -4.4 -5.2 -5.9 -4.5
73
???????? ?????YMDD????
-????52-104???HBV DNA?????????(??????)
PAA N120 PAA N120 AAA N240 AAA N240 AAP N120 AAP N120
YMDDv ?YMDDv YMDDv ?YMDDv YMDDv ?YMDDv
??HBV DNA106??/ml???? 23 93 52 182 18 98
52? 23/23 100 89/92 97 50/52 96 168/179 94 3/18 17 22/97 23
104? 21/22 95 84/90 93 47/52 90 152/166 92 18/18 100 84/96 88
74
???????? ?????YMDD????-??????ALT????52-104?ALT?
????(??????)
PAA N120 PAA N120 AAA N240 AAA N240 AAP N120 AAP N120
YMDDv ?YMDDv YMDDv ?YMDDv YMDDv ?YMDDv
??ALT ???? 22 86 49 178 17 93
52? 19/22 86 55/85 65 40/49 82 136/175 78 1/17 6 22/92 24
104? 20/21 95 60/84 71 40/49 82 124/161 77 15/17 88 62/91 68
75
???????? ?????YMDD????-????52-104???HBeAg????(2
??)?????(??????)
PAA N120 PAA N120 AAA N240 AAA N240 AAP N120 AAP N120
YMDDv ?YMDDv YMDDv ?YMDDv YMDDv ?YMDDv
??HBeAg?????? 23 96 50 187 18 97
52? 0/23 0 21/95 22 4/50 8 15/183 8 1/18 6 7/96 7
104? 1/22 5 25/93 27 5/50 10 27/169 16 5/18 28 18/95 19
76
???????? ADV??????

• 0-52???????HBV DNA???????????1 log10
  ?45????104?????????
• 52-104???141????ADV??????HBV DNA???????????1
  log10,???104?????????
• ??149????????(37??????????????????)
• ????
• 52?????ADV????????
• 104??N236T?????3?(??153?430?481),A181V?????3?(??15
  9,58?110)??6?????AAA?,ADV??????1.3(6/480)?

77
?????-????

• ?104??,PAA??AAA??AAP????????HBVDNA?????????????-5.
  3? -5.0?-4.7 log10??/??,
• ?52???,104?HBV DNA??????
• ?52??,PAA??AAA??AAP??????HBVDNA??????????????-5.0?
  -4.5?-0.2 log10??/???

78
?????-????

• ?104??,PAA??AAA??AAP?????94?91?89???HBVDNA?????
  ??
• ?104??,PAA??AAA??AAP?HBVDNA??????45?42?41,?52??
  ?,104?HBVDNA???????
• ?52??,PAA??AAA?HBVDNA??????30?28?1?

79
?????-????

• ?104??,PAA??AAA??AAP?ALT????????76?78?71,?52???
  ,104?ALT?????????
• ?52??,PAA??AAA??AAP?ALT????????69?79? 21?
• ?104??,PAA??AAA??AAP?ALT???????0.6xULN,??????1xULN
  
• ?52??,PAA??AAA??AAP?ALT????????0.7xULN?0.6xULN?3.
  0xULN?

80
?????-????

• ?104??PAA?AAA?AAP?HBeAg???,???30?19?28,?52?????
  
• ?52??PAA?AAA?AAP?HBeAg??????20?13?9?
• ?104??PAA?AAA?AAP?HBeAg?????(???),???23?15?20,?
  52?????
• ?52??,PAA?AAA?AAP?HBeAg?????(???)???18?8?7?
• ?104??PAA?AAA?AAP?HBeAg?????(???),???22?15?20,?
  52?????
• ?52??,PAA?AAA?AAP?HBeAg?????(???)???17?8?5?

81
?????-????

• ????????,PAA?,AAA? ?AAP????14(17/120),
  7(17/240)?13(16/120)???????HBeAg?????
• ??,AAP????52-104???????ADV???,????????????????,?10
  4???????????PAA??AAA????

82
?????-?????

• ?????????????????????????????? 5?????????
• ??????????????????????????????,???????????????????
  ??????????
• ?????1.7(8/474)??????????????????????????????????
  ????
• ?????????????????,0.6(3/474)????????????,2???????
  ??1????????

83
?????-?????

• ??????????????????????????????
• 1.7(8/474)?????????????????gt0.5mg/dL??????,??5???
  ????????,?5???????????
• ???????????????lt1.4mg/dL????

84
?????-???????

• ??????104??????????????
• ??52???,????104?????????????
• ??52???,AAP?104???????????????????

85
?????-????????????

• ADV???????,??6/480(1.3)??ADV?????HBV DNA???
• ???????,????YMDD?????????????ADV?????YMDD??????,??
  ?ADV?????????????
• ????YMDD????????????????????

86
??

• ?????,?ADV??????,??ADV10mg ??1??????HBeAg???????
  ??????????????????,?????????,?????

87
? ?!
88
?????????--???????????
?????? ??? ??
89
????

• ???????????????????????????????????/????????,????1
  
• ????????????????2
• ????????????HBV,??????????????,??????,????????????
  ???HCC????????,???????????????3
• ?????????????,?????????????4

1. APASL Guideline 2005, 2. AASLD Guideline 2004,
3. ??????????2005, 4. A Treatment Algorithm for
the Management of CHB Virus Infection in the US
90
??????

• ??????????1,2,3
• (1) ?????ALT?AST?????????2
• (2) ?????HBeAg??-HBe?HBV DNA????????2,3
• (3) ??????,??????????????????????2
• (4) ????????????1??????2,3
• (5) ????????????-HCV,?-HDV,AFP?3
• ?????????????????/?????/?????????????1
• ???????/???????????????????????1

1. APASL Guideline 2005 2. ??????????2005 3. A
Treatment Algorithm for the Management of CHB
Virus Infection in the US
91
????SFDA??????

• ?????????????,???????????(ALT?AST)???????????
  ??????????????????????

????????
92
?????????

• HBeAg???????????1,2,3,4
• HBV DNA???1?105??/ml,ALT??210ULN?,?ALTlt2ULN????
  ????G2?/?S2?????3
• HBV DNA?????1?105??/ml?,?????3??,HBV
  DNA????,?ALT??3
• ???????????????1,2,3,4
• ????HBV DNA????,?ALT???????,??????????????4
• HBeAg???????????1,2,3,4
• ????????1,2,3,4
• HBV DNA???????????1,2,3,4
• ??????????????2,3
• ???????????????????3
• ??HIV?????????1,4

1. APASL Guideline 2005, 2. AASLD Guideline 2004,
3. ??????????2005, 4. A Treatment Algorithm for
the Management of CHB Virus Infection in the US
93
?????????

• HBeAg???????????1,2,3,4
• HBeAg???????????1,2,3,4
• HBV DNA???1?104??/ml,ALT????????2ULN?,???????????
  ???? (G2?/?S2) 3
• ?????????,?????????????,?????3,4
• ????????1,2,3,4
• HBV DNA???????????1,2,3,4
• ??????????????2,3
• ???????????????????3
• ??HIV?????????1,4

1. APASL Guideline 2005, 2. AASLD Guideline 2004,
3. ??????????2005, 4. A Treatment Algorithm for
the Management of CHB Virus Infection in the US
94
?????????

• HBeAg???????????1,2,3,4
• HBeAg???????????1,2,3,4
• ????????1,2,3,4
• ???????????????1,2,3,4
• HBV DNA???????????1,2,3,4
• ??????????????2,3
• ???????????????????3
• ??HIV?????????1,4

1. APASL Guideline 2005, 2. AASLD Guideline 2004,
3. ??????????2005, 4. A Treatment Algorithm for
the Management of CHB Virus Infection in the US
95
?????????

• HBeAg???????????1,2,3,4
• HBeAg???????????1,2,3,4
• ????????1,2,3,4
• HBV DNA???????????1,2,3,4
• HBeAg??????HBV DNA ?1?104??/ml?????????4
• ??????????,?????????????,?????3,4
• ??????????????2,3
• ???????????????????3
• ??HIV?????????1,4

1. APASL Guideline 2005 2. AASLD Guideline 2004
3. ??????????2005 4. A Treatment Algorithm for
the Management of CHB Virus Infection in the US
96
?????????

• HBeAg???????????1,2,3,4
• HBeAg???????????1,2,3,4
• ????????1,2,3,4
• HBV DNA???????????1,2,3,4
• ??????????????2,3
• ??????????????,?????????????????????,???????2
• ???????????????????3
• ??HIV?????????1,4

1. APASL Guideline 2005, 2. AASLD Guideline 2004,
3. ??????????2005, 4. A Treatment Algorithm for
the Management of CHB Virus Infection in the US
97
?????????

• HBeAg???????????1,2,3,4
• HBeAg???????????1,2,3,4
• ????????1,2,3,4
• HBV DNA???????????1,2,3,4
• ??????????????2,3
• ???????????????????3
• ????????????,???????3
• ??HIV?????????1,4

1. APASL Guideline 2005, 2. AASLD Guideline 2004,
3. ??????????2005, 4. A Treatment Algorithm for
the Management of CHB Virus Infection in the US
98
?????????

• HBeAg???????????1,2,3,4
• HBeAg???????????1,2,3,4
• ????????1,2,3,4
• HBV DNA???????????1,2,3,4
• ??????????????2,3
• ???????????????????3
• ??HIV?????????1,4
• HBV?HIV????????????????HBV?HIV????14?4
• ?????????HIV??,????10mg??HIV??????,????????1,4

1. APASL Guideline 2005, 2. AASLD Guideline 2004,
3. ??????????2005, 4. A Treatment Algorithm for
the Management of CHB Virus Infection in the US
99
????????

• ?????????????????????1
• ???????1?,??10mg ,?????????1
• ????????????????1
• ???????????????,??????,???3?????HBV
  DNA???????????2

1.???????? 2. ??????????2005
100
???????

• ??????????????????,???????????1,2
• (1) ????????????1?,??3?,?????????3??1?1,2
• (2) ???????????3????1?HBsAg?HBeAg??-HBe?HBV
  DNA1,2
• (3) ??????,????????????????????????2
• (4) ????????????2

1. APASL Guideline 2005 2. ??????????2005
101
?????

• HBeAg???????????
• ????1?1,2,3
• ?HBV DNA ?ALT??,HBeAg???????-HBe?,??????,??HBeAg??
  ??????????6??????2?,??????6??,HBeAg???????HBV DNA
  (PCR?) ?????,????1,3,4
• ?????????HBeAg???????????,???????????????4

1. APASL Guideline 2005, 2. AASLD Guideline 2004,
3. ??????????2005, 4. A Treatment Algorithm for
the Management of CHB Virus Infection in the US
102
?????(?)

• HBeAg???????????
• ????1?1,2,3
• ?????,?6??????HBV DNA (PCR?)?ALT4
• ???3? (??????6??) HBV DNA (PCR?)
  ????ALT???????1,3

1. APASL Guideline 2005, 2. AASLD Guideline 2004,
3. ??????????2005, 4. A Treatment Algorithm for
the Management of CHB Virus Infection in the US
103
?????(?)

• ????????
• ??????????,?HBeAg????????????????HBV
  DNA??(PCR??)?HBeAg?????????6??1
• HBV DNA???????????
• ?????,?????1,2
• ???????HBV DNA??(PCR??)?HBsAg??2

1. ??????????2005, 2. A Treatment Algorithm for
the Management of CHB Virus Infection in the US
104
?????????????

• ????????????2???????????HBV DNA????????????1log10
  2
• ?????HBeAg????1?2?3??????????0?1.6?3.1
  ,??HBeAg???????0?3.0?5.9111
• ??????????,?????1???6????????2
• ??????????,????????2

1. ??????????2005, 2. A Treatment Algorithm for
the Management of CHB Virus Infection in the US
105
?????????

• ?????,????????,?????????2????1?ALT?AST??????
  (???)?HBV??????HBV DNA,???36????1?,????12????????
  ????,???????1,2
• ???????????,??????????3

1. APASL Guideline 2005, 2. ??????????2005,
3.????????
106
? ?!
107
????????????????

• ??????????????
• ??? ??

108
???????
??????
??????
109
???????
??????
??????

• ????????
• ???????????

110
????????????????????
12 HBeAg ?? ????? ?????612? ??????
HBeAg 12
??????
HBeAg- 40
HBeAg 48
????????
??????
88 ???????????????? (gt 1 yr)??
111
HBeAg????????????
112
????ALT??????5??HBeAg????
???? HBeAg?? ? HBeAb??
Guan, et al. 2002
113
????? 5 ?HBeAg ?????
M ???? O ?????
O5
O44
O1
O1
15/55 M0
18/49 M6
26/51 M4
32/52 M3
30/50 M5
5/155 M0
11/134 M0
17/150 M0
27/152 M5
26/155 M2
114
??????2?????HBeAg?HBVDNA???

• ???HBeAg????HBVDNA?????????????? 24 ? (???
  85)
• ????????2?

????
6 months
1 year
31
2 years
???
21
16
15
13
11
HBV DNA ??
HBeAg ??
Ryu et al. J Hepatology. 200339614-619.
115
??????????????
100
70
75
53
42
50
?????YMDD ??,
24
25
0
0
??
1 (n 335)
2 (n 93)
3 (n 58)
4 (n 58)
?
Lai et al. Clin Infect Dis. 200336687.
116
?????? (3 ?) ??????? (??????)

• 63?????????????HBeAg???,???? 2?
• 65 ????????
• ?YMDD?????YMDD?????????????????
• 8/11????????, 12/19?????????? ????????????
• ???? YMDD??????????
• - 3???????????????YMDD gt 2?

Dienstag et al. Gastroenterology. 2003124108.
117
????????(3?)???????
Dienstag et al. Gastroenterol 2003
118
??????????????????

• 651?????9??????41???
• ????44?
• HBeAg ? HBeAg-
• Ishak ?? 4
• ? 21?????????????
• ???? ???????
• CPT?? 2, HCC, SBP, ??????, ??????
• ??????,32 ? (??, 0-42 ?)
• ?????????????

Liaw et al. N Engl J Med. 20043511521-1531.
119
???????????????????
Liaw et al. N Engl J Med. 20043511521-1531.
120
???????????????
25
??? (n215)
21
YMDD?? (n209) (49)
20
??? (n221)
???
???????
15
13
YMDD??
10
5
5
???
0
0
6
12
18
24
30
36
???????? (?)
Liaw et al, NEJM 2004
121
HBeAg?????????????
122
?????????HBV DNA????ALT???
48? (n 171)
96? (n 85)
144? (n 65)
100
80
80
73
63
60
48
??,
40
40
29
20
0
?? HBV DNA lt 1000 ??/mL
ALT ??
Kaplan-Meier estimates of time to confirmed event
Marcellin et al. EASL 2005. Abstract 73.

123
???????????HBeAg?????
48? (n 171)
96? (n 85)
144? (n 65)
100
80
60
53
46
46
??,
40
33
23
20
14
0
HBeAg ????
HBeAg ??
Kaplan-Meier estimates of time to confirmed event
Marcellin et al. EASL 2005. Abstract 73.

124
??????????

• ????48??144????PCR?????HBVDNA (gt 1000
  ??/mL)???????
• 144??ADV ?????? (3, 2/65)

Marcellin et al. Hepatology. 200440655A.
125
HBeAg??????????????
126
??????4?HBeAg????
0
N 94
100
83
0/7 ?? ????
75
66
60
59
50
39
40
??,
34
25
8
0
12
24
36
48
?
22
74
42
94
n
Gaia et al. Aliment Pharmacol Ther. 2004 20 287.
127
????????HBeAg????

• ???,???????
• ??4???201?HBeAg??????????????
• 209 ??????????????
• 195 ?????????????
• ????????

Papatheodoridis et al. Hepatology.
200542121-129.
128
Papatheodoridis G V,et al.HEPATOLOGY
200542121-129
129
Papatheodoridis G V,et al.HEPATOLOGY
200542121-129
130
Papatheodoridis G V,et al.HEPATOLOGY
200542121-129
131
Papatheodoridis G V,et al.HEPATOLOGY
200542121-129
132
HBeAg????????????????????????

• ?????
• 20????????
• 656 ???????HBeAg????????
• ???????????22?

Di Marco et al. Hepatology. 200440883-891.
133
HBeAg????????????????????????

• ??????????????????????
• 17.7???????????????
• ???? (n 17) CTP A ??? (n 15) CTP B/C ??? (n
  5)
• ?????????????????????????????? (P lt .001)
• ?????????????????CPT B/C???CPT A?????? (P lt .001)
• ?????????????????????? (P lt .001)
• ?4????????? 22.1

Di Marco et al. Hepatology. 200440883-891.
134
??????HBeAg????????????

• 50??????????????
• ????HBVDNA???2?,???????
• ??????HBVDNA???????????
• 6 ??, 94 12 ??, 88
• 18 ??, 78 24 ??, 74
• 27 ?HBV DNA???????2??????
• 12 ?????????
• ???????, 4.5?
• 7 ????????
• ???????, 12 ?

PCR????
?????, HBV DNA?? (PCR) ????, ??????HBV DNA ????
ALT gt 1.5 x????
Fung et al. J Viral Hepat. 200411432-438.
135
HBeAg???? ???????????
136
???????HBeAg???? 240?
?5? ADV (5???)
?4? ADV (4???)
0
Wk 48
Wk 96
Wk 144
Wk 240
?? (4??? ADV ??)
????
?? (4??? ?1? ADV)
??
??
ADV 10 mg/? ??48??????21?????.
?????????????. ???????
Hadziyannis et al. AASLD 2005. Abstract 72492.
137
HBeAg???????????????5 ?

• 5???5????HBsAg??

?? HBV DNA lt 1000 ??/mL
ALT ??
100
78
80
77
75
75
72
71
69
68
67
67
60
??,
40
20
0
48
96
144
192
48
96
144
192
240
240
????(?)
n 69 58 69 65 55 64
53 64 59 55
Hadziyannis et al. EASL 2005. Abstract 492.
Hadziyannis et al. AASLD 2005. Abstract 72492.
138
4??5?????????????????????

• 5??gt 50 ?????????????

??
??
??
??,
4? (n 22)
5? (n 24)
4? (n 22)
5? (n 24)
????
???
ADV4 ??5?????????????? Knodell????????? -4.5?
-5.0 ????? Ishak ??????????? -1.0
Hadziyannis et al. AASLD 2005. Abstract 72492.
139
4??5??????Ishak ?????
Ishak ??????? 1? ?????
80
17/24 (71)
P .005
60
12/22 (55)
40
??,
20
0
0
1
2
3
4
5
????????
Cochran-Armitage?????5???????????? 1
?????????????.
Hadziyannis et al. AASLD 2005. Abstract 72492.
140
??????????????
?????? ??? ??
141
?????????????
???? ???? III????? II?????
????? ???? ???? ???? Emtricitabine ???? Elvucitabine Valtorcitabine Amdoxovir Racivir LB80380
?????? ????? ???? Alamifovir Pradefovir
???? a-??? Peg-??? a-2a
???????HIV?? ?????III?????
142
???????

• ?????(Genotypic Resistance) ?????????????HBV?????
  
• ?????(Virologic Rebound) ????????,?? HBV DNA????
• ????(Clinical Breakthrough) ???????ALT???????????
  
• ????(Phenotypic Resistance)
• ??????????????????,????????
• ????
• ????(Cross Resistance) ???????????,?????????????

143
??????????
HBV DNA???
A
B
C
D
D
V173L L180M M204I/V
LAM1 / FTC2
A181V
N236T
ADV3
T184A/G/I/S S202G/I M250V
ETV4
M204I
LdT5
A194T
TDF6
??????????????YMDD??????
1. Allen et al. Hepatology. 1998 271670-1677.
2. Gish et al. J Hepatol. 20054360-66. 3. Qi et
al. J Hepatol. 200440(Suppl 1)20-21. 4. Tenney
et al. AAC. 2004483498-3507. 5. Lai et al.
Gastroenterology. 2005129528-536. 6. Sheldon
et al. Antivir Ther. 200510727-734.
144
??????

• ???????,?????????????????
• ????????????

???? ???? ????
?????? (L180M M204V) ??????? (N236T) ??????? (A181V)
????????????????????? ???? ???? ???? ???? Elvucitabine ???? ???? ???? ????
?????????? ????? ???? ???? ???? ???? ???? ????
????????? ??????????, ????????
1. Zoulim F. Antiviral Res. 200464(1)1-15. 2.
Brunelle et al. Hepatology. 2005411391-1398. 3.
Locarnini et al. EASL 2005. Abstract 36.
145
???????????????
Response
Genotypic
Phenotypic
600
45
40
500
35
400
30
25
BIL(?mol/L) ALT(IU/L)
300
20
200
15
10
100
5
0
0
ADV
Lamivudine
146
??????????
Genotypic / Phenotypic
????
LAM
ADV
?????
?
ETV
LdT
????
TDF
?
147
???????????????

• ????
• ??????????????,96??????????0(48????19??????)
• ??????????,??48??????????7,96??10
• ????
• ?????(?)?????????,??????????????52???????4.5

????????
100
?????
????
80
70
60
53
???????
42
40
29
24
18
20
11
2
0
0
1
3
4
5
2
?????
??????5?????
1. Lai et al. Clin Infect Dis. 200336687-96 2.
Colonno et al. Hepatology 200440 661A. 3. Xiong
et al. EASL 2005. 4. Gish et al. AASLD 2005.
Abstract 67146. 5. Sherman et al. AASLD 2004.
Abstract 1152.
148
???????????????

• HBeAg???????1
• ????????2
• ?????????3
• ???????????4,5
• ???????????????6

1. Leung et al. Hepatology. 2001331527-1532.
2. Dienstag et al. Gastroenterology.
2003124105-117. 3. Liaw et al. N Engl J Med.
20043511521-1531. 4. Yuen et al. J Hepatol.
200339 850-855. 5. Si Ahmed et al. Hepatology.
200032 1078-1088. 6. Mutimer et al. Gut.
200046107-113.
149
??????????????????????????

• ??????3???????????????
• ???????HCC????3.9 ,??????7.4
• Hazard? 0.49 P 0.047
• YMDD ???????????
• ??????????,49?????YMDD??
• ???????????13,?????????????5

Liaw et al. N Engl J Med. 20043511521-1531.
150
?????????????????
25
??? (n215)
21
YMDD?? (n209) (49)
20
??? (n221)
???
???????
15
13
YMDD??
10
5
5
???
0
0
6
12
18
24
30
36
???????? (?)
Liaw et al, NEJM 2004
151
????????????

• 1. ??
• 2. ??
• 3. ??
• 4. ????????

152
?????????????

• ????????????
• ???????????????
• ????????????????,
• ??????????????
• ????????
• ?????
• ???????????,???????????

1. Richman J Virol. 2001271670-1677. 2. Zoulim
Antivir Res. 2004 641-15.
153
???????????????????
???????????
100
80
60
?????,
34
40
20
18
20
11
2
1
0
LAMPeg
LAMPeg
LAM
LAM
LAM
LAMADV
Lau3
Sung1
Marcellin2
1. Sung et al. J Hepatol. 2003 38(suppl
2)25-26. 2. Marcellin et al. N Engl J Med.
2004 3511206-1217. 3. Lau et al. Hepatology.
200440171A.
154
???????

• ??HBV DNA ????????
• ?????PCR????HBV DNA
• ?????????????
• ????????????
• ??????
• ?????? ???6????
• ?????/??? ?3????
• ?????
• ??????????????????????????????????,???????????????
  ?

1. Locarnini et al. Antivir Ther.
20049679-693. 2. Keeffe et al. Clin
Gastroenterol Hepatol. 2004.287-106.
155
?? ???????

• ???????
• ??HBV DNA?????????????????,?? 1.0 log
• ???HBV????????????
• ???
• ??????????
• ??HBV?????????????
• ????????????????? (????)

1. Locarnini et al. Antivir Ther. 20049
679-693. 2. Brunelle et al. Hepatology.
2005411391-1398.
156
?????????????
Response
Genotypic
Phenotypic
600
45
40
500
35
400
30
25
BIL(?mol/L) ALT(IU/L)
300
20
200
15
10
100
5
0
0
ADV
Lamivudine
157
?????

• ?????????????1
• ?????????????2
• ??????????3

???????

• ????????ALT?????4,5
• ????????????6

??????

• ??????????????7
• ??????????6

??????
1. Leung et al. Hepatology. 2001331527-1532.
2. Liaw et al. N Engl J Med. 2004 3511521-1531.
3. Delaney et al. AAC. 2001121-35. 4. Gish et
al. J Hepatol. 200440(suppl 1)127. 5. Peters
et al. Gastroenterology. 2004126 91-101. 6.
Zoulim Antivir Res. 2004 641-15. 7. Chin et
al. AAC. 2001 45 2495-2501.
158
????????????????

• ???????
• ??????
• ?????????????
• ????????
• ????? ???????????????????1
• ???? ?N236T?????2?A181V???????
• ???? ??????????????? ???????????????????3

1. Westland et al. J Virol Hepatiti.s
2004111-7. 2. Xiong et al. J Hepatol. 2003
38(suppl 2)182. 3. Sherman et al. Hepatology.
200440(suppl 1) 664A.
159
??????????????

• ???????????
• ????????????????????????
• ???????????????
• cccDNA???????,??????????????
• ??????????????????????????

??????????????
1. Richman Hepatology. 200032866-867. 2.
Zoulim et al. Hepatology. 2003381353-1355. 3.
Maynard et al. J Hepatol. 200542 279-281. 4.
Zoulim et al. Antiviral Chem Chemother.
200415299-305.
160
??????????????

• ????????????????????? ????????????????,??????????1
  
• ??,??????????????????,???????????????????
• ??????????????????? (??)
• ?48??,????????5.11 log10 ??/mL
• ?48??,?????????7

1? 2? 3?
?435 460i???,??????????? 0/131 2/144 0/76
2??????????????????????,????????
,?????????????????????
1. Zoulim et al. EASL 2005. Abstract 545. 2.
Maynard et al. J Hepatol. 2005. 42279-281. 3.
Peters et al. Gastroenterology. 200412691-101.
4. Xiong. EASL 2005. Abstract 36. 5. Sherman et
al. AASLD 2004. Abstract 1152.
161
?????????????
???????
???,?????????????
???? ????? ???? ???? Peg???
???? ?????? ?????
?????? (?????) ??????????
162
??

• ??????,????????????
• ????????
• ????????????
• ???????????????????????
• ??????????????????????
• ???????????????
• ??????????????????,??????
• ????????????????
• ?????????????

163
(No Transcript)
164
? ?