報告人：朱郁芬

A Comparison of Entecavir and Lamivudinefor HBeAg-Positive Chronic Hepatitis BA Comparison of Entecavir and Lamivudinefor HBeAg-Positive Chronic Hepatitis B

Hepatitis B virus VirologyHepatitis B virus Virology

Partially ds DNA genome, 42nm 4 genes – HBsAg, HBcAg, HBV

Pol/RT, X protein Serologic marker of HBV infection:

HBsAg Serologic markers of HBV replication:

HBeAg, HBV DNA, HBV Polymerase

Middle surface antigen（ HBsAg ）

Nucleocapsid（ HBcAg ）

DNApolymerase

Envelope（ HBsAg ）

Small surface antigen（ HBsAg ）

Large surface antigen（ HBsAg ）

Genomic DNA

RNA primer

Hepatitis B virus VirologyHepatitis B virus Virology

HBsAg envelopes

Partially double-stranded DNA

A(n)

Infectious HBV virion

(-)-DNA

Infectious HBV virion

mRNAcccDNA

DNA polRT

Encapsidated pregenomic mRNA

Replication cycle for HBVReplication cycle for HBV

How HBV cause diseaseHow HBV cause disease

Acute HBV infectionAcute HBV infection

90% neonates 25–30% children

<10% adults

Progressive chronic hepatitis

Progressive chronic hepatitis

CirrhosisCirrhosis

HCCHCCDeathDeathDecompensated cirrhosis

Decompensated cirrhosis

Inactivecarrier state

Inactivecarrier state

EASL Consensus Guidelines. J Hepatol 2003; Lok, McMahon. Hepatology 2004 (AASLD Guidelines)

Chronic infectionChronic infection

15–40%

Fulminant hepatic failure

Fulminant hepatic failure

~2%

Hepatitis B ProgressionHepatitis B Progression

< <> >HBeAg +ve HBeAg -ve/ anti-HBe +ve

ALT

HBV-DNA

Normal/mild CH

Moderate/severe CH Moderate/severe CHNormal/mild CH

Cirrhosis

Inactive-carrier state HBeAg -ve Chronic hepatitis

HBeAg +ve Chronic hepatitis

Immune tolerance

Immune clearance

Low replicative phase

Reactivation phase

Cirrhosis

109–1010 cp/mL107–108 cp/mL

<105 cp/mL

>105 cp/mL

Inactive cirrhosis

Stages of Chronic HBV Infection

Adapted from Fattovich. Sem Liver Dis 2003

The Global DiseaseThe Global Disease

WHO and CDC fact sheets, available at www.who.int and www.cdc.gov

Half of the world’s population lives in an area with high Half of the world’s population lives in an area with high HBV prevalenceHBV prevalence

World population

6 billion

2 billion with evidence of

HBV infection

300–400 million with

chronic HBV

25% die of cirrhosis or liver cancer

Prevalence of chronic HBV Prevalence of chronic HBV carriers in different carriers in different

countriescountries

From: World Health Organization. Introduction of hepatitis B vaccine into childhood immunization services, 2001, Geneva, WHO, WHO/v&B/01.31

HBsAg Endemicity

8% and above – High

2% - 8% - Intermediate

Below 2% - Low

Treatment ： Entecavir ＆ LamivudineTreatment ： Entecavir ＆ Lamivudine

HBV study important recordHBV study important record

1965 find virus antigen 1970 find virus particle 1973 find polymerase in virus particle 1974 atomic structure for restriction enzyme 1976 treat for IFN-α 1977 find -antigen in liver cell 1982 know HBV replication 1986 reassembled HBV vaccine 1993 Lamivudine clinical try 1999 Lamivudine Approvable 2002 PEG - clinical try 2005 Entecavir Approvable

New Approval MedicineNew Approval Medicine

Interferon Intron A ： recombinant interferon α-2b ；

made by Schering-Plough

Nucleotide analogue Lamivudine ； made by GlaxoSmithKline Entecavir ； made by Bristol-Myers Squibb Adefovir dipivoxil ； made by Gilead Sciences

Intron AIntron A

簡介： 使 HBV 活性減低，降低發生肝硬化、肝癌機會。 作用機制： Interferon 由受感染的細胞所產生，刺激其

他未受感染的細胞進入抵抗病毒，產生許多 antiviral effector molecules ，因而改變細胞表面蛋白質抗原的組成，使得細胞不易感染；另一方面受干擾素刺激的細胞會活化 RNAse-L ，將 mRNA 分解；還能磷酸化 eIF2 ，降低轉譯的效率，干擾病毒蛋白質的合成。關於其作用機制尚有很多不清楚的地方。

副作用：產生像感冒般的症狀，掉頭髮，情緒不穩定，抑制骨髓造血功能，肝衰竭等等

使用限制：需同時符合以下 3 項條件 HBsAg （＋）超過六個月及 HBeAg （＋）超過三個月。 ALT 值介於正常值上限五倍以上（ ALT≧5X ）。 無肝功能代償不全。

Interferon signal transductionInterferon signal transduction

Adefovir DipivoxilAdefovir Dipivoxil

簡介： Adefovir 原本是一種治療 HIV 的藥物，後來研究發現對於抑制 HBV 也有療效。 Adefovir 可抑制 HBV 複製，改善肝功能指數及肝組織發炎。

作用機制：進入細胞後， adefovir 會直接和 HBV 的 DNA 聚合酶結合，抑制 HBV 的複製。

副作用：極少，產生抗藥性的機率低，但長期服用可能產生腎臟方面的問題

LamivudineLamivudine

簡介： Lamivudine 是一個化學合成的核苷類似物，本來是用來治療愛滋病毒的，在較低劑量時也能對抗HBV ，故而有醫師將之用來治療慢性 B 型肝炎。

作用機制：可以抑制病毒反轉錄酵素，阻斷病毒 DNA的合成而抑制病毒的複製。

副作用：極少，但較易產生抗藥性 可被迅速良好吸收 使用限制：需同時符合以下 2 項條件

HBsAg （＋）超過六個月及 HBeAg （＋）超過三個月。 ALT 值大於或等於正常值上限五倍以上（ ALT≧5X ），或已

發生肝代償不全者（有黃膽且凝血酶原時間超過三秒）。

HBsAg envelopes

Partially double-stranded DNA

A(n)

Infectious HBV virion

(-)-DNA

Infectious HBV virion

mRNAcccDNA

DNA polRT

Encapsidated pregenomic mRNA

Replication cycle for HBVReplication cycle for HBV

LamivudineLamivudine

EntecavirEntecavir

簡介：對 HBV 有極高的專一性（體外試驗發現 entecavir 對其他病毒幾乎沒有影響）。體外試驗發現它對病毒的抑制效力是 Lamivudine 的 30倍，且對 Lamivudine 抗藥性病毒株也有效。

作用機制：可以抑制病毒反轉錄酵素，阻斷病毒 DNA的合成而抑制病毒的複製。

副作用：極少

MethodMethod

double-blind trial 715 patients with HBeAg+ chronic hepatiti

s B who had not previously received a nucleoside analogue.

0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks.

Test: histologic improvement. serum HBV DNA level, HBeAg loss and seroc

onversion, and normalization of the alanine aminotransferase level.

Histologic improvement Histologic improvement

entecavir group (72 %). lamivudine group (62 %). P = 0.009

PCR 、 ALT 、 Serum DNA & HBeAg seroconversionPCR 、 ALT 、 Serum DNA & HBeAg seroconversion No viral resistance to entecavir was d

etected. Safety was similar in the two groups

ResultsResults

ResultsResults

ConclusionsConclusions

Among patients with HBeAg-positive chronic hepatitis B, the rates of histologic, virologic, and biochemical improvement are significantly higher with entecavir than with lamivudine. The safety profile of the two agents is similar, and there is no evidence of viral resistance to entecavir.

The end

N

N

N

N

NH2

O

PO

O

O

O

O

O

O

N

N

N

N

NH2

O

PO

HO

HO

N

N

N

N NH2

O

OP

O

HO

OHHO

Esterases

Deoxyadenosine monophosphate

(dAMP)

Adefovir Dipivoxil

Adefovir (PMEA)

Adefovir Dipivoxil: an oral prodrugfor Adefovir, a synthetic acyclic dAMP analogue

HBV多聚酶模型HBV多聚酶模型

核苷酸结合槽