?Professor: Graham Cooksley

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1 (??) &

/TTB

84Niederau NEJM 1996MonthsMonths1.00.80.60.40.224364860728412243648607212IFNHBeAg 1.00.80.60.40.2IFNHBeAgP=0.004*P=0.018**According to the proportional hazards modelIFNHBeAg

2005

IFNalfa-2a (40KD)

:EASL = 1APASL = , 2a 2* (2005)AASLD = , 3 (03/2006) =, 2a ,, (12/2005)

* IFN or PEG-IFN for ALT 25 x ULN only; lamivudine for ALT 25 x ULN and >5 x ULN

EASL Consensus Statement. J Hepatol 2003 (EASL Guidelines); 2. Liaw et al. Liver International 2005 (APASL Guidelines Update); 3. Lok and McMahon. Hepatology 2004 (AASLD Guidelines) 4. Chinese HBV guideline. CJH 2005

Tenofovir*Emtricitabine* Telbivudine* Clevudine* Others... X ovir, Y vudine, Z ythum

* Not currently approved

1 HBeAgLok and McMahon. 2004; Chang et al. EASL 2004; Chang et al. AASLD 2004; Chang et al. APASL 2005; Dienstag et al. N Engl J Med 1999; Lai et al. N Engl J Med 1998; Shiffman et al. EASL 2004bDNAPCR A

4vs 4 () 00.7012243648HBV Niederau NEJM 19960.10.20.30.40.50.60102030405060701 (158/995)2 (134/773) (%)16%17%23%28%3 (148/654)4 (155/561)Data from Lok Gastroenterology 2004alfa-2b 4

1 HBeAgAASLD Guidelines Lok, McMahon. Hepatology 2004; Shouval et al. AASLD 2004; Hadziyannis et al. Hepatology 2000; Tassopoulos et al. Hepatology 1999; Shiffman et al. EASL 2004* By PCR

HBeAgLok. N Engl J Med 2005; Lai et al. APASL 2005

* : 6 < ~700,000 /mLALT

HBeAgHBV DNA6

502PCRHBV DNA6ALT PCR +ve Digene +ve and ALT >1.5 x ULNFung et al. J Viral Hepat 2004PCR60.00.20.40.60.81.002456101214161824232220137No. at risk:27Proportion of patients with relapse 30%-50%PCRHBV DNA 6

* YMDDLok et al. Gastroenterology 2003; Hadziyannis et al. N Engl J Med 2005; Tassopoulos et al. Hepatology 1999; Santantonio et al. J Hepatol 2000; Rizetto et al. J Hepatol 2003; Locarnini et al. EASL 2005; Colonno et al AASLD 2004; Lampertico et al. EASL 2004; Hadziyannis et al. AASLD 2005

1 45 1 45 1 4 HBeAg23%6571%0%NA0% (6%*)NAHBeAg1339%63%0%1828%0% (6%*)NA

1HBsAg (LAM, ADV)2,3 (LAM, ADV)3 ( (ADV)4,5

1. Honkoop et al. J Hepatol 2002; 2. Liaw et al. J Gastro Hepatol 2002; 3. Fung. DDW 2005; 4. Schiff et al. Hepatology 2003; 5. Chang et al. J Hepatol 2003

Peginterferon alfa-2a (40KD)

HBeAgAlfa-2a IFN*12%28%24%* (%)4.5 MIU IFN-2a180 g

n=51n=46PEG-IFN2an=143 P=0.036* 24HBeAg, HBV DNA

Alfa-2a : IIIHBeAg1 ITT: n=814HBeAg2 ITT: n=537 100 mg qd2a 180 g qw + 100 mg qd2a 180 g qw + qd0244824 7248 72 1. Lau et al. N Engl J Med 2005; 2. Marcellin et al. N Engl J Med 2004

alfa-2a HBeAg

HBeAg24HBeAg 32%19%

HBeAg (%) ++27%n=271n=271n=272P=0.232 (OR = 0.8)P=0.023 (OR = 1.6)P

HBeAg HBeAg (%)27%24%20%32%27%19%++P=0.023P

HBV DNAHBeAg12*all numbers shown are log10 reduction from baseline32%27%19%P=0.023P

HBV DNA HBV DNA

alfa-2a HBeAg

59%44%(%) PEGASYS + PEGASYS + 60%n=177n=179n=181P=0.004HBeAg24 ALT 24 (72)

Marcellin et al. N Eng J Med 2004

(%) n=177n=179n=18143%29%44%P=0.849P=0.003P=0.007PEGASYS + PEGASYS + * HBV DNA

24HBsAg Lau et al. N Engl J Med 2005; Marcellin et al. N Engl J Med 2004P=0.029** Fishers

+ (n=271)+ (n=271)

(n=272)

HBeAg (%)8 (3%)8 (3%)0 (0%)

(n=177)(n=179)(n=181)HBeAg (%) 5 (3%) 3 (2%)0 (0%)

: ?

: ?6121212 ( 33% ALT >10xULN Hadziyannis NEJM 2005)()350% 414-18%

* () ***** 1. Lau et al. AASLD 2004; 2. Marcellin et al. N Eng J Med 2004

PEGASYS + PEGASYS +

HBeAg(+) 1n=2710n=2713*n=2721**HBeAg(-)2n=1771***n=1790n=1810

644F3/4 vs 2:1

2ChildPughSBP

Liaw et al. N Engl J Med 2004

(n=221)YMDD (n=209) (49%) ()0510152025061218243036: YMDD (%) (n=215)5%13%21%Liaw et al. N Engl J Med 2004

?

ChildPugh

2211 (

ChildPugh

2211 (

: ?1 (3),

2.

3. 4. ()5. 1. 2. 3.

4. 5.

-2a IFN

HBeAg *

/

*or IFN contraindicated / not tolerated

:HBsAg

alfa-2a HBeAg (ALT/ DNA)

CHB :2,5-TTTTBDNAOn-treatment Response to Nucleos(t)ide Analogue Therapy for HBeAg-negative CHBAs would be expected from agents with a purely antiviral mode of action, the nucleoside/tide analogues have a significant effect on HBV DNA levels on-therapy. Overall, the rates of HBV DNA suppression, ALT normalisation and improvement in histology are similar for lamivudine and adefovir. Results suggest that entecavir has superior efficacy to lamivudine and adefovir in terms of on-treatment HBV DNA suppression and ALT normalisation.It is important to remember that these are ON TREATMENT results. Treatment cessation is associated with viral rebound, ALT flare and reactivation of disease, and the sustained response rate for both lamivudine and adefovir is less than 10%. Nucleoside/tide analogues are therefore long-term, maintenance therapy, where optimal treatment duration is unknown.

Treatment cessation with NAs is associated with viral rebound, ALT flare and reactivation of disease, and the sustained response rate for both lamivudine and adefovir is less than 10%. Nucleoside/tide analogues are therefore long-term, maintenance therapy, where optimal treatment duration is unknown.PEGASYS provides a more durable response.

Treatment cessation with NAs is associated with viral rebound, ALT flare and reactivation of disease, and the sustained response rate for both lamivudine and adefovir is less than 10%. Nucleoside/tide analogues are therefore long-term, maintenance therapy, where optimal treatment duration is unknown.PEGASYS provides a more durable response.

24(72)HBeAg ()HBeAg ..Lau et al. AASLD 2004

HBeAg HBeAg .,.,36. ,.24,HBeAg .Lau et al. AASLD 2004HBV DNAHBeAg, DNAHBV DNA,7.2 log,5.8,4.5. ,HBV DNA. 24,HBV DNA2.4 log.HBeAg. Lau et al. EASL 2005HBeAg(-)ALT24 PEGASYS (PEGASYS +/- ) ALT PEGASYS 60%

Marcellin et al. N Eng J Med 2004

HBeAg(-)HBV DNA24PEGASYS (PEGASYS +/- )HBVDNA(HBV DNA < 20,000 copies/mL) PEGASYS

Marcellin et al. N Eng J Med 2004

HBsAg seroconversion is often considered the ultimate goal of therapy since it is associated with positive long-term clinical outcomesWhile HBsAg seroconversion was achieved in 3% of patients treated with PEGASYS of PEGASYS + LAM, no case of HBsAg seroconversion was reported following LAM monotherapyHBeAg(+) 1HBeAg(+)HBeAg(-)PEGASYS21. Lau et al. AASLD 2004; 2. Marcellin et al. N Eng J Med 2004

Time to Disease Progression According to YMDD Mutant StatusAround half the patients treated with lamivudine developed YMDD mutations which were associated with virological breakthrough and an increased likelihood of disease progression in terms of increased Child-Pugh score. However, clinical endpoints among patients with YMDD mutants occurred at a lower frequency than among patients receiving placebo.

. HBeAgIFN/