CHIN LC IU TR VIM GAN B MN GIAI ON HIN NAY

TS.BS. Phm Th L HoaBM Nhim, HYD TP HCM

20/12/2014

NI DUNG

I. TNH HNH IU TR NHIM HBV HIN NAY

II. MC TIU V NHNG THCH THC CA IU TR

III. CHIN LC IU TR V CC BIN PHP TR LIU MI

TRONG THP NIN TI

IV. NHNG IM ANG THAY I TRONG TR LIU

400 triu ngi nhim HBV, 750.000 cht hng nm do bnh l lin quan vi HBV.

>60% nc ang pht trin

2 chin lc iu tr chnh:

iu tr c thi hn bng IF hay PEG-IFN

iu tr lu di vi NAs

nh gi p ng iu tr? Ngng thuc? HBeAg m?

Cc phc kt hp tr liu? D bo p ng?

THUC IU TR C HIU C T 1992 (LAM 4 NHM NAs nhiu NAs mi

IU TR KHI cn l thch thc. cccDNA tn lu ko di trong gan.

TI HOT; TI PHT; X GAN; VIM GAN BNG PHT... CN L MI E DA

TNH HNH CHUNG V IU TR VIM GAN B MN

YU T NH HNG N DIN TIN T NHIN

Liaw et al, Liver Int 2006:26, 472-489Fattovich et al. J Hepatol 48, 2008:335-352

Kao JH, Hepatol Int 2007

VIRUS HBV

t bin1762/1764, PreS

Genotype C>B D>ATi lng virus

HBsAg nh lng

K CH

Nam, Tui >40Gim min dch

(nng, a c hiu)Tng ALT nhiu tHot tnh vim trn

m hc

YU T KHC

Ru bia, Thuc lTip xc Aflatoxin

ng nhimHIV/HCV

Tiu ngBMI cao

Tng tin trin bnh l gan do HBV

X GAN/UNG TH GAN

YU T K CH TRN DIN TIN T NHIN NHIM HBV

Thursz et al. Seminar Liver dis 2011

THI TR NHIM HBV KO DI

Tnh a hnh lin quan

PHN NG CYTOKIN

TNF-863A TNF-238A

TNF-308A

IL-10R K47E

C TNH HLA HLA NHM I: A*0301HLA NHM II:

DRB1*1301

DRB1*1302

HLA NHM I: B*08

HLA NHM II:

DR7 (DRB1*07)

DR3 (DRB1*07)

DQA1* 0310

DQA1* 0510

DRB1* 1201

II. MC TIU V

NHNG THCH THC CA IU TR

MC TIU IU TR CHUNG

AASL 2009C CH KO DI SAO CHP HBV V PHC HI BNH L GAN

EASL 2012C CH LU DI SAO CHP CA HBV.CI THIN CHT LNG SNG/ KH NNG SNG CN QUA:

Phng nga din bin x gan, mt b gan, bnh gan giai on cui, UTG vt vong.

APASL 2012C CH LIN TC SAO CHP HBVT P NG BN VNG (DURABLE)

Phng nga din bin x gan, mt b gan, UTGTng t l , thi gian sng cn

Liaw YF Hepatol Int 2012:6:531-561Lok AS. Hepatol 2009; AASLD practice GuidelinesEASL Jury; J Hepatol 2012:167-185

MC TIU IU TR C TH

TRONG IU TR

Sinh ha: ALT

Chuyn i huyt thanh HBeAg v HBsAg

c ch sao chp (HBVDNA m khng ng ngha thi tr hon ton HBV)

M hc: Ch s phn ng vim (A) v x ha (F)

LU DI:

Ci thin x ha, x gan: Lm sng, Fibroscan, Tiu cu, ...

Nga Ung th gan

Tit tr HBV (mt HBsAg)

HAI CHIN LC IU TR VIM GAN B MNQUY TC NGNG IU TR

THI GIAN C NH

CHUYN I HBeAg

MT HBsAg

Liaw YF Hepatol Int 2012:6:531-561Lok AS. Hepatol 2009; AASLD practice GuidelinesEASL Jury; J Hepatol 2012:167-185

KHNG P DNG CHO MT B GAN

C CH NH IU TR

3. NAs KO DI

C THI HN

2. NAs NGN HN

1. C THI HNIFN

Chuyni HBeAg

ALTMt

HBeAgGim

HBVDNAm

HBVDNA

VIM GAN B MN HBeAg DNG

DU HIU CH NG CA P NG IU TR

ALTGim

HBVDNAm

HBVDNA

VIM GAN B MN HBeAg M

GimqHBsAg

MtHBsAg

GimqHBsAg

MtHBsAg

MC TIU

NGN NGA: SUY GAN MNB.GAN G CUI

X GANHCC

CI THIN:CHT LNG SNG

T VONG

MC X HA GAN

NGNG IU TR

NAs: C CH VIRUS KHNG IU TR KHI

NHM THUC C CH SAO CHP:

Kim sot virus lu di (ON-TREATMENT EFFECT)

c ch sao chp ca polymerase (gim, m ha HBVDNA)

Rt him chuyn i HBsAg

HN CH:

S DNG KO DI khng thuc HN CH S DNG KO DI

Khng tc dng trn cccDNA KHNG THI TR HON TON

Chng gen: t bin S/PreS T BIN TRN THOT VCCIN (VAMs)

Khng ci thin khim khuyt trong p ng min dch

LAM ADV ETV TDF

PHC IU TR: C TH HA TR LIU

Liaw YF Hepatol Int 2012:6:531-561Lok AS. Hepatol 2009; AASLD practice GuidelinesEASL Jury; J Hepatol 2012:167-185

KHNG P DNG CHO MT B GAN

C CH NH IU TR

3. NAs KO DI

C THI HN

2. NAs NGN HN

1. C THI HNIFN

T L P NG; TD PH

TI PHT, KHNG THUC

THI GIAN C NH

CHUYN I HBeAg

MT HBsAg

QUY TC NGNG IU TR

III. CC TR LIU MI TRONG THP NIN TI

CHIN LC IU TR

CHIN LC HIN NAYN TR HAY PHI HP IU TR ?

C S L LUN:

Chu trnh HBV phc tpMULTI-TARGET ? (Lao, HIV, ...)

PHI HP NAs: Hiu qu tc thi cao, p ng HT ?

PHI HP NAs + IU HA MIN DCH: P NG VIRUS +

CHUYN I HUYT THANH CAO HN

Trnh t phi hp?

NAs no phi hp?

Tnh hung no nn?

CC NAS MI ANG HA HN

NHM THUC TNH TRNG

NAsC CH

POLYMERASE

CLEVUDINE CHA

EMTRICITABINE FDA (HIV)

AMDOXOVIR II(HIV)

LB80380 IIb

TENOFOVIR ALAFENAMIDE (GS 7340) II/III

CC TR LIU ANG HA HN

NHM THUC TNH TRNG

C CH XM NHP MYRCLUDEX-B Ib/IIa

C CH TO V TIT CORE/CAPSID BAY 41-4109 IGLS-4, NVR-1221 TIN LS

HAP: Heteroaryldihydropyrimidines

C CH SN XUT, CHUYN M cccDNA

GS9620 TIN LS

Cc ZFP, DSS, IFN-Lymphotoxin- receptors

C CH PHNG THCH HBsAg Rep 9 AC IINITAZOXANIDE II

IU HA MIN DCHTIT CYTOKIN PEG-IFN LAMDA I

HOT HA TLR-7, TLR-3 GS 9620 TIN LS

P NG LYMPH T CORE ANTIGEN VACCIN I

KCH THCH LYMPH T TIT IFN- ePA-44 II

RNA INTERFERENCE ARC 520 I

HI-8 HBV II

CC TR LIU CA TNG LAI

Tc dng chng xm nhp (entry): (Myrcludex-B): l lipopeptide tng hpca vng pre-S1, nhm vo NTCP (Natri Taurocholate Co-transported

Peptide).

Tc dng trn qu trnh to capsid: HAP: Hetero-Aryldihydro-Pyrimidines: c ch to capsid, to capsid bt

thng, mt n nh v d b hy hoi.

Phenypropenamide: c ch qu trnh kt hp nn virion, hnh thnhcc virion bt thng (virion trng)

Tc dng trn qu trnh tit HBsAg: Nitazoxanide and Tizoxanide: gim HBsAg, HBeAg ngoi bo v HBcAg

ni bo.

Nucleic acid polymer, Amphipathic oligonucleotide (Rep 9AC)

Tc dng trn qu trnh bc v (encapsidation):

Glucosidase inhibitors: c ch glycosyl ha protein v ti li ni bo (ER) nh

hng s hnh thnh v bc, to nn tiu th Dane bt thng, khng c kh

nng gn vo mng t bo khi pht s xm nhp.

Tc dng trn cccDNA (GS-9620 ): cccDNA trong nhn c thi gian bn hy 33-50

ngy, khng b nh hng bi NAs, l cu trc duy tr tnh di truyn ca HBV.

Thuc to cccDNA li, HBV khng thuc, ti hot sau ngng thuc.

Bt hot/ thi tr/ ging ha cccDNA: cc ZFP (Zinc Finger Protein. Ngn cn

chuyn m ca cccDNA.

Ngng biu hin gen cccDNA (Epigenetic Silencing of cccDNA): c ch biu l

v chc nng ca cccDNA

Tc dng trn mRNA

CC TR LIU CA TNG LAI

Tc dng trn k ch:1. Kch hot TLR Agonists: ung, hp thu nhanh gan, c th sn xut vin phi

hp vi NAs. Kch thch sn xut IFN, cytokin tc dng trn qu trnh truyn tnhiu trong t bo. Thuc tc dng chnh ti gan, trnh c phn ng ton thndo hot ha phn ng khng c hiu.

2. Cytokines

CYT107: l IL-7 ngi ti t hp th h 2. phc hi min dch mnh; dngnh ph gia cho vcxin. Tc dng tt cho iu tr truyn t bo.

Recombinant IL-21: l cht iu ha min dch mi ang pha I v II tr liucho bnh nhn ung th. mt thuc phi hp tt vi NAs.

3. Programmed Death-1/PD Ligand-1: Phc hi trng thi kit qu ca lymph T, phc hi min dch thch ng BN vim gan B mn.

4. Vc xin tr liu:

Protein v ti t hp: HBsAg v HBcAg hay vc xin ti t hp khc Adeno-virus-based Therapeutic Vaccine: TG 1050 DNA & T-cell Peptide Epitope

CC TR LIU CA TNG LAI

CHNG XM NHP (MYRCLUDEX):

Nhm vo NTCP (Sodium Taurocholate

co-transported

peptide)

CHNG TO CAPSID: HAP: Heteroaryl-dihydro-pyrimidinesPhenypropenamide

c ch to capsid, to capsid bt thng, KHNG n nh.

TC DNG TRN QU TRNH BC V: Glucosidase inhibitors: c ch glycosyl ha cc protein v, to cc virion khim khuyt khng c kh nng gndnh gy nhim trng

CHNG TIT HBSAG:Nitazoxanide, TizoxanideGim HBsAg, HBeAg ngoi bo

CHNG cccDNA: cccDNA TG bn hy di(3350 ngy), d tr cccu trc gen t bin

TC DNG TRN mRNA v TC DNG TRN K CH kch thch tit IFN, cytokin

TLR Agonist PD-21, GS-9620, CYT107, IL-7, IL-21, Therapeutic Vaccin: TG 1050, DNA & T-cell Peptide Epitope VACCIN

CC V TR TC DNG CA TR LIU HBV