CẬP NHẬT điều TRỊ VIÊM GAN b c

VẪN NÊN ĐIỀU TRỊ ! Tiên lượng tốt ngắn hạn không bảo đảm cho tiên lượng tốt về lâu dài  Tải lượng siêu vi cao kéo dài đe doạ nguy cơ ung thư gan... VẪN NÊN ĐIỀU TRỊ ! Tiên lượng tốt n

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2018 AASLD – HBeAg (+)

Terrault Hepatology 2018;67:1560

ALT > ULN but < 2 x ULN ALT ≥ 2 x ULNALT ≤ ULN

Noncirrhotic HBeAg-Positive Patients With CHB

HBV DNA 2000-20,000 IU/mL may represent seroconversion

 Monitor HBV DNA every 1-3 mos

̶̶ Treat if HBV DNA > 2000 IU/mL persists for > 6 mos

HBV DNA > 20,000 IU/mL

 Treat

HBV DNA > 20,000 IU/mL

 Exclude other causes of ALT elevation

̶̶ Treat if ALT elevation persists,

especially if > 40 yrs of age

 Evaluate fibrosis/inflammation

̶̶ Treat if ≥ F2/A3

HBV DNA > 20,000 IU/mL

 Monitor ALT and HBV

DNA every 3-6 mos,

HBeAg every 6-12 mos

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HBV DNA < 2000 IU/mL

 Exclude other causes of ALT elevation and evaluate fibrosis/inflammation

̶̶ Treat if ≥ F2/A3

2018 AASLD – HBeAg (-)

Terrault Hepatology 2018;67:1560

HBV DNA ≥ 2000 IU/mL

 Monitor ALT and HBV DNA

every 3 mos for 1 yr, then

Any Detectable HBV DNA

 Exclude other causes of ALT elevation

̶̶ Treat if ALT elevation

persists with HBV DNA

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HN GAN CHÂU ÂU 4-2019

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HN GAN HOA KỲ 11/2019

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CÁC CHỈ ĐIỂM MỚI CỦA NHIỄM HBV

‒ Products of the precore/core

gene, share identical sequence

of 149 amino acids

HBV RNA[5]

 Serum HBV RNA: có thể là một chỉ điểm theo dõi điều trị kháng HBV

 Quy trình chưa hoàn toàn được chuẩn hoá

cccDNA: not consistent

1 Wong Liver Int 2017;37:995 2 Hadziyannis Genes (Basel) 2018;9:469 3 Wong J Clin Microbiol

2007;45:3942 4 Kimura J Biol Chem 2005;280:21713 5 Liu Hepatology 2018;[Epub].

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HBcrAg

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 HBcrAg: correlates with intrahepatic cccDNA

 Predict HBeAg) seroconversion

 Predict persistent responses before and after cessation of nucleos(t)ide analogues, potential HBV reactivation and risk of hepatocellular

carcinoma progression or recurrence

 new potential therapeutic affect intrahepatic cccDNA are under

development: the monitoring of HBcrAg might be useful to judge

therapeutic effects

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NÊN MỞ RỘNG CHỈ ĐỊNH ĐIỀU TRỊ HAY KHÔNG?

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Should Patients With

Immune-Tolerant CHB Be Treated?

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AASLD Guidance on Immune-Tolerant CHB

 “The AASLD recommends against antiviral therapy for adults with

immune-tolerant CHB”

 “The AASLD suggests antiviral therapy in the select group of adults

‒ > 40 yrs of age with normal ALT and elevated HBV DNA (1 million IU/mL)

‒ liver biopsy specimen showing significant necroinflammation or fibrosis”

Terrault Hepatology 2018;67:1560.

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KHÔNG NÊN ĐIỀU TRỊ !

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VẪN NÊN ĐIỀU TRỊ !

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 Tiên lượng tốt ngắn hạn không bảo đảm cho tiên lượng tốt về lâu dài

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 Tiên lượng tốt ngắn hạn không bảo đảm cho tiên lượng tốt về lâu dài

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 Tải lượng siêu vi cao kéo dài đe doạ nguy cơ ung thư gan

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 Điều trị vẫn có thể làm giảm đáng kể HBV DNA

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 Việc chuyển từ gđ dung nạp MD sang gđ hoạt động MD không rõ ràng

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TỶ LỆ XƠ HOÁ GAN TIẾN TRIỂN Ở BN MEN GAN BT

 10% of HBeAg-positive patients with normal ALT have advanced fibrosis

Wong Clin Gastroenterol Hepatol 2009;7:227.

Advanced Fibrosis by FibroScan

LSM > 9 kPa (normal ALT) or > 12 kPa (elevated ALT)

ALT ≤ ULN (n = 80) ALT > 1 to 2 x ULN (n = 127) ALT > 2 to 5 x ULN (n = 196) ALT > 5 x ULN (n = 50)

10

20

26

30

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 Việc chuyển từ gđ dung nạp MD sang gđ hoạt động MD không rõ ràng

 Một số bn ALT bình thường vẫn có thể gây xơ hoá gan

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THAY ĐỔI QUAN ĐIỂM ĐỐI VỚI GĐ DNMD?

Wong Clin Mol Hepatol 2018;24:108.

suggest treating such patients may reduce the risk of liver

fibrosis progression and hepatocellular carcinoma.”

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ĐỀ XUẤT ĐỐI VỚI BN GĐ DNMD HIỆN NAY

 Cá nhân hoá

 Bn gđ DNMD nhưng có tiền sử gia đình UTG: nên điều trị

 Đã điều trị thì nên kéo dài

 Khuyến cáo phối hợp (eg: 2 NA)

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VACCIN VIÊM GAN B MỚI

 This recombinant single-antigen formulation with a unique CpG

adjuvant is the first new HBV vaccine approved for US adults in > 25 yrs

‒ Requires 2 doses (vs 3 doses for previously available vaccines)

‒ Can be completed in 1 tháng (vs 6 tháng )

Schillie MMWR Morb Mortal Wkly Rep 2018;67:455 Schillie MMWR Recomm Rep 2018;67:1.

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KHÓ KHĂN TRONG ĐT VG B ?

High viral burden

Weak immune response

Persistence

of cccDNA

B-cells

CD8+ T-cells PD-1

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CÁC ĐIỀU TRỊ ĐANG NGHIÊN CỨU

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TẠO CAPSID

Adaptive Immunity

T-Cells B-Cells

Hepatocyte

Effect Through IFN-γ or Cytotoxicity

HBV DNA Integration

Transcription cccDNA Formation

rcDNA cccDNA

Nucleus

pgRNA AAA

AAA AAA AAA mRNA

pgRNA

ER

DNA+

DNA-Encapsidation

& Reverse Transcription

Positive Strand Synthesis

Viral Protein Secretion

HBeAg HBsAg

Innate Immunity

NK Cells Other

Cells

Translation

Zoulim Cold Spring Harb Perspect Med 2015;5:a021501.

ABI-H0731 Core inhibitors

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Studies 201/202: ABI-H0731 for Treatment-Naive and

Virologically Suppressed Patients With CHB

 ABI-H0731: investigational HBV core inhibitor

 Interim analysis of 2 double-blind, placebo-controlled phase IIa trials

Ma EASL 2019 Abstr LB-06.

 Primary endpoint: Wk 24 log10

decline in HBsAg or HBeAg

 Primary endpoint: Wk 12 and 24 log10 decline in HBV DNA

Randomized 3:2 Randomized 1:1

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Studies 201/202: Primary Endpoints

Ma EASL 2019 Abstr LB-06.

Study 201: Virologic Outcomes Study 202: HBV DNA Decline

Treatment Wk

ETV + ABI-H0731 ETV + placebo

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New Targets for HBV: Translation

T-Cells B-Cells

Hepatocyte

rcDNA cccDNA

Nucleus

pgRNA AAA

AAA AAA AAA mRNA

pgRNA

ER

DNA+

HBeAg HBsAg

Innate Immunity

NK Cells Other

Cells

Translation

JNJ-3989 Inhibition of protein translation by siRNA

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AROHBV1001: JNJ-3989 for Patients With CHB

 JNJ-3989 (formerly ARO-HBV): 2 hepatocyte-targeted RNAi molecules that interfere with cccDNA, integration-derived transcripts

 Interim analysis of open-label CHB cohorts from phase II trial (N = 40)

‒ Patients received 3 subcutaneous JNJ-3989 doses; if NA naive, started

NA treatment at Day 1; if experienced, continued baseline NA

Yuen EASL 2019 Abstr PS-080 Gane AASLD 2018 Abstr LB-25 NCT03365947.

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AROHBV1001: HBsAg Reduction With JNJ-3989

Yuen EASL 2019 Abstr PS-080.

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New Targets for HBV: cccDNA

T-Cells B-Cells

Hepatocyte

rcDNA cccDNA

Nucleus

pgRNA AAA

AAA AAA AAA mRNA

pgRNA

ER

DNA+

HBeAg HBsAg

Innate Immunity

NK Cells Other

Cells

Translation

cccDNA silencing ZFNs, TALENs, CRISPR/Cas9

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Strategies to Control or Eliminate cccDNA

Pharmacological

(small molecules)

Immune

control

Enhance host factors

Lok Hepatology 2017;66:1296 Asadi CP Allergy and Immunology 2018;1:001

Gene therapy

(nucleases)

cccDNA

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New Targets for HBV: HBsAg

T-Cells B-Cells

Hepatocyte

rcDNA cccDNA

Nucleus

pgRNA AAA

AAA AAA AAA mRNA

pgRNA

ER

DNA+

HBeAg HBsAg

Innate Immunity

NK Cells Other

Cells

Translation

HBsAg release inhibitor REP 2139, REP 2165

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REP 401: First-line NAPs for HBeAg-Negative CHB

 REP 2139: investigational NAP that prevents assembly/release of subviral particles

from integrated HBV DNA or cccDNA, blocks replenishment of circulating HBsAg

 Open-label, randomized phase II trial

‒ Patients received REP 2139 or, if showing poor HBsAg response to TDF + pegIFN in

Wks 24-48, were rescued with REP 2165 (amenable to high-frequency dosing)

Tx-naive patients with

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REP 401: Antiviral Activity of First-line NAP Treatment

HBV DNA

 TDF-associated decreases in HBV DNA not affected during therapy

 Anti-HBs levels markedly increased when pegIFN added,

but only in those whose HBsAg decreased to < 1 IU/mL

Bazinet Global Hepatitis Summit 2018 Abstr O-018

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New Targets for HBV: RIG-I

T-Cells B-Cells

Hepatocyte

rcDNA cccDNA

Nucleus

pgRNA AAA

AAA AAA AAA mRNA

pgRNA

ER

DNA+

HBeAg HBsAg

Innate Immunity

NK Cells Other

Cells

Translation

Immunomodulators RIG-I agonist (eg, inarigivir)

IFN

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ACHIEVE: First-line Inarigivir for Patients With CHB

suppresses viral replication by countering interaction of HBV pol with pgRNA

 Final analysis of dose escalation cohorts from phase II trial (Wks 1-24)

HBsAg+ without treatment for > 6 mos;

HBV DNA > 2000 IU/mL if HBeAg-

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200 mg

ACHIEVE: HBV DNA Decline With Inarigivir

Yuen EASL 2019 Abstr GS-12.

*

* *

*P < 01 vs placebo.

2 0 -2 -4 -6 -8

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New Targets for HBV: NTCP

T-Cells B-Cells

Hepatocyte

rcDNA cccDNA

Nucleus

pgRNA AAA

AAA AAA AAA mRNA

pgRNA

ER

DNA+

HBeAg HBsAg

Innate Immunity

NK Cells Other

Cells

Translation

Entry inhibitors Bulevirtide

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MYR203: Bulevirtide for Chronic HBV/HDV Coinfection

cells with strong inhibitory potential against HBV/HDV coinfection

 Final analysis of multicenter, open-label phase II trial

Patients positive for serum HDV RNA,

anti-HDAg (≥ 6 mos), HBsAg;

HBeAg positive or negative;

ALT ≥ ULN but ≤ 10 x ULN;

Bulevirtide 5 mg + PegIFN

(n = 15)

Bulevirtide 2 mg

(n = 15)

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MYR203: Antiviral Activity of Bulevirtide

Wedemeyer EASL 2019 Abstr GS-13.

Undetectable HDV RNA ALT Normalization HBsAg Response*

P = 0209 P = 0022

Wk 48 Wk 72 Wk 48 Wk 72 Wk 48 Wk 72

PegIFN Bulevirtide 2 mg + pegIFN Bulevirtide 5 mg + pegIFN Bulevirtide 2 mg

*Either HBsAg undetectability or ≥ 1 log IU/mL reduction † Includes HBsAg loss in 26.7% of patients.

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RNA INTERFERENCE-BASED TRIPLE COMBINATION THERAPY

RNA interference:

- silences hepatitis B viral RNA transcripts from integrated hepatitis B viral DNA and episomal cccDNA

Class N capsid assembly modulator (normal empty capsids):

- Blocks HBV replication & cccDNA formation in preclinical models

- Shown to reduce hepatitis B viral DNA and RNA

EASL 2019.

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A total of 12 patients

+ class N capsid assembly modulator 250 mg/d for 12 w

+ NA

HBsAg: Mean reductions were 1.4 ± 0.12 on day 85 (n = 12) and 1.8 ± 0.11)

in 7 patients with day 113 data

Additive/synergistic antiviral effects, possibly increasing functional cure

rates after finite treatment

RNA INTERFERENCE-BASED TRIPLE COMBINATION THERAPY

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CẬP NHẬT ĐIỀU TRỊ VIÊM GAN C

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WHO HCV Elimination Targets

WHO Draft WHO Global Hepatitis Strategy, 2016-2021

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 JJ Feld et al NEJM, 31/12/2015

 nucleotide polymerase inhibitor (sofosbuvir )

 NS5A inhibitor (velpatasvir)

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GT 1 ASTRAL-1

GT 2 ASTRAL-1/

ASTRAL-2

GT 3 ASTRAL-3

GT 4 ASTRAL-1

GT 5 ASTRAL-1

GT 6 ASTRAL-1

Đánh giá chung SVR 1-6 ASTRAL-1, -2, -3

GT: Genotype hay còn gọi là kiểu gen

Thông tin kê toa Epclusa ® - Việt Nam

gan còn bù

Feld JJ, et al N Engl J Med 2015; 373 (27): 2599-2607

Foster GR, et al N Engl J Med 2015; 373(27): 2608-2617

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% SVR12 được điều trị bởi EPCLUSA ® (12 tuần/ASTRAL-1)

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EPCLUSA ® + RBV /12 w/ BN XƠ GAN MẤT BÙ

a SVR12 là tiêu chí chính và được định nghĩa là HCV RNA <15 IU/mL ở 12 tuần lễ sau khi kết thúc điều trị.2 Đạt SVR được xem như sạch virus.

b Không có đối tượng nào nhiễm HCV genotype 5 hoặc 6 HCV được điều trị với EPCLUSA và ribavirin trong 12 tuần Curry MP,

et al N Engl J Med 2015; 373 (27): 2618-2628

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TỶ LỆ TÁI PHÁT THẤP - KIỂU GEN 1-6

EPCLUSA ®

Đối chứng ASTRAL-1 (GT 1, 2, 4, 5, 6) EPCLUSA ® /12 TUẦN GIẢ DƯỢC

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Các phản ứng phụ (mọi cấp độ) được báo cáo ở ≥5% số đối tượng (ASTRAL-1)

EPCLUSA® AN TOÀN VỚI TỈ LỆ BỎ ĐIỀU TRỊ THẤP QUA CÁC THỬ NGHIỆM LÂM SÀNG

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FDA NEWS RELEASE- JUNE 28, 2016

Hepatitis C virus infection

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Sofosbuvir/velpatasvir for 12 weeks in HCV with

end-stage renal disease undergoing dialysis

Phase II, single-arm study, 59 patients with genotype 1–6 HCV infection with ESRD undergoing hemodialysis or peritoneal dialysis

Received open-label (400 mg/100 mg) once daily for 12 weeks

sofosbuvir/ velpatasvir

Results: Overall, 56 of 59 patients achieved SVR12 (95%)

Conclusions: Treatment with sofosbuvir/velpatasvir for 12 weeks was safe and effective in patients with ESRD undergoing dialysis

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PAN- GENOTYPE !

 FDA approves sofosbuvir/velpatasvir/voxilaprevir (Vosevi) second-line DAA HCV treatment in the US in the US - 01/8/2017

 FDA Approval of MAVYRET™ (glecaprevir/pibrentasvir) for the

Treatment of Chronic Hepatitis C in All Major Genotypes (GT 1-6) in as

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With A30K

Pangenotypic Regimens: GLE/PIB for 8 Wks in Patients Without Cirrhosis

1 Zeuzem NEJM 2018;378:354 2 Asselah Clin Gastro Hepatol 2018;16:417.

break-5 relapse

2 lost to f/u

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Can We Avoid Genotyping?

 It’s a delicate balancing act

cost, delay, and complexity

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Can We Avoid Genotyping?

 It’s a delicate balancing act

cost, delay, and complexity

A Reasonable Compromise

Genotype only for:

Cirrhosis Treatment-experienced

(DAA/IFN)

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Pangenotypic HCV Regimens for Treatment-Naive

Patients Without Cirrhosis

Regimen constituents Protease inhibitor/NS5A inhibitor NS5B inhibitor/NS5A inhibitor

Select DDI

considerations Anticonvulsants, statins, St John’s wort, warfarin

Anticonvulsants, proton pump inhibitors, rifampin, St John’s wort,

warfarin

Contraindications  Severe hepatic impairment (CP C)Concurrent ATV or rifampin use  Do not use with RBV in patients with RBV contraindication

Warnings/precautions  HBV reactivation risk  HBV reactivation riskBradycardia with amiodarone

coadministration

GLE/PIB [package insert] SOF/VEL [package insert].

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CÁC VẤN ĐỀ SAU ĐIỀU TRỊ

 Consequences of liver disease

‒ Only an issue with cirrhosis (fibrosis assessment pretreatment!)

‒ HCC risk

‒ Liver function – MELD purgatory

 Reinfection risk

‒ Ongoing exposures – HCV RNA testing every 6-12 mos

‒ No ongoing exposures – annual ALT, promote liver health (diet & alcohol), and nothing else!

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TÓM TẮT VỀ HCV

 HCV assessment and treatment are now simple

 Assessment can be limited to fibrosis staging (still required in all

patients before treatment!), HBV and HIV testing, and drug-drug

interaction review

 Genotyping limited to treatment-experienced & and cirrhosis

 Pangenotypic regimens for most if not all settings

 Post-SVR follow-up limited to HCC surveillance for those with cirrhosis and HCV RNA for those with ongoing risk exposures

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