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Chronic hepatitis B Guideline of treatment
소화기내과 신현필
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Chronic Hepatitis B Inactive HBsAg Resolved Hepatitis B
Carrier State Resolved Hepatitis B Chronic Hepatitis B HBsAg (+) > 6 months HBsAg (+) > 6 months Previous known history of acute or chronic hepatitis B HBeAg(+) CHB: HBV DNA >20,000 IU/ml (105 copies/mL) HBeAg(-) CHB: >2,000 IU/ml (104 copies/mL) HBeAg (–), anti-HBe(+) HBV DNA <2,000 IU/ml (104 c/mL) anti-HBc ±anti-HBs HBsAg (-) Persistently normal ALT/AST levels Undetectable HBV DNA Liver biopsy: absence of significant hepatitis Normal ALT levels Persistent or intermittent elevation in ALT/AST levels Immune tolerant phase HBsAg(+), HBeAg(+) High HBV DNA > 2,000 IU/ml Liver biopsy : chronic hepatitis with moderate or severe necroinflammation Normal ALT/AST levels Liver biopsy : No or mild necroinflammation Definition & diagnostic criteria of HBV infection. AASLD Practice guideline 2009 대한간학회 만성B형간염 진료 가이드 라인 2011
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Natural course B형 간염 바이러스 한국 3% C형 간염 바이러스 한국 0.8-1.7% 급성 간염 만성보유자
급성 간염 90% 수직감염90-95%예방 80-90% 만성보유자 1-10% 성인 (정상면역) 5%/년 5년 20% 20-30% 간경변증 2-4%/년 2-4%/년 간암
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HBsAg prevalence Genotype C2형 – HBeAg seroconversion,
유병률(%) Start HBV vaccination since 1985* Universal HBV vaccination for newborn infants since 1995 연령 Genotype C2형 – HBeAg seroconversion, LC & HCC, IFN, 재발율 *대한간학회 만성B형간염 진료 가이드 라인, 국민건강영양조사 2010
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HBV Chronic infection
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Natural course in vertical transmission
대한간학회 가이드라인, 2011 1. Immune tolerance 2. Immune reactive 3. Inactive HBV carrier 4. HBeAg(-) CHB 5. HBsAg clearance HBeAg(+) HBeAg(–) >104 cp/mL <104 cp/mL HBV-DNA 105–108 cp/mL 109–1010 cp/mL ALT chronic HBV infection 경과지만 모두 같지 않다 Immune tolerant phase patients are HBeAg+, HBV DNA level is high but ALT is normal 면역 관용기- 높은 HBV DNA 농도에도 간손상 별로 없어, genotype C, eAg자발 loss 적어 가임기 여성 The Immune clearance phase is characterized by elevated ALT 면역제거기- 중등도 이상 염증 반응. HBcAg 혹은 HBeAg에 대한 독성 T 림프구의 공격 HBeAg 재양전, 음전 반복- inactive carrier state- HBeAg(-) CHB In some patients this is followed by spon HBeAg seroconversion and Patients enter into inactive carrier state with normal ALT and very low HBV DNA In other patients, the immune clearance phase is protracted with recurrent hepatitis flares leading to severe hepatitis and cirrhosis Not all patients who enter the inactive carrier state stay that way Some develop reactivation of HBV replication but remain HBeAg- Many of these patients have precore or core promoter HBV variants that prevent or decrease HBeAg production These patients have e-CHB 비활동성시기- 6개월마다 check eAg(-) CHB- Mutation으로 eAg생성 못해 HBsAg loss-> 1년 1-2% 빈도, 우리나라 0.5%미만 Monitor Treat Monitor Treat Monitor HBsAg(+) asymptomatic carrier HBeAg(+) chronic hepatitis Inactive (carrier) state HBeAg(–) chronic hepatitis HBsAg clearance Yim et al. Hepatology 2006
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Compact genomic structure of HBV
The C gene codes HBeAg, a soluble, secreted protein (initiation from the pre-C region) HBcAg, the intracellular core protein (initiation after pre-C). Pre-core/core 유전자 HBcAg과 HBeAg 생성에 관여 HBV부분적 이중가닥 DNA 구조- 4개의 유전자가 surface, core, polymerase, X 단백을 coding Pre-core/core 유전자는 뉴클레오캡시드(nucleocapsid) 단백인 B형간염중심항원(hepatitis B core antigen: HBcAg)과 뉴클레오캡시드 단백의 분비형인 HBeAg을 생성한다
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Precore mutant & core-promoter mutation
Precore mutants : HBeAg이 precore component 에서 translation되는 것을 막는다 Core-promoter mutants : precore mRNA의 down-regulated transcription prevents transcription of the coding region for HBeAg and yields an HBeAg-negative phenotype
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HBeAg(-) chronic hepatitis B
HBeAg(-)시: HBV DNA virions/mL 넘지 않아 치료시 undetectable level, withdrawal(-) 만성 간염 HBV DNA ≥ 2,000 IU/mL (104 copies/mL) 특히 지중해, 유럽, 아시아 등 non-genotype A Precore, core-promoter mutation이 자연 경과 후반기 발생 (어릴때 감염, 40-55세 사이, HBeAg(+)보다 고령) More progressive liver injury : cirrhosis, HCC
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Target of CHB treatment
만성 간염 단계에서 HBV 증식 억제 염증 완화, 섬유화 방지 간경변증, 간암 진행하는 것을 방지 임상 지표: ALT의 정상화, HBV DNA(-), HBeAg의 혈청소실 혹은 혈청 전환, 조직소견호전 HBsAg loss: 이상적
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2. Inactive HBsAg carrier Sustained immune control
Ideal gain 1. HBsAg clearance 2. Inactive HBsAg carrier Sustained immune control 3. HBV DNA suppression
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HBeAg (+) CHB treatment
HBV -DNA ALT 치료 방침 + <20,000 IU/mL 정상 미치료, 정기적 관찰, 의미 있는 조직학적 변화시 치료 고려 ≥ 20,000 IU/mL 1-2배 HBeAg의 seroconversion 적다 젊은 환자 : 면역 관용기 흔함 (수직감염) Liver Biopsy : 40세 이상 환자에서 HCC 가족력± ALT 2배 근접 지속 (EASL≥ 20,000) 2배 이상 (EASL≥ ULN) 치료 시작 (ETV, TDF, Peg IFN) -혈청전환과 황달 등 고려 간생검 결과 – 중등도 이상의 염증괴사나 Periportal fibrosis Based on practice guidelines of the American Association for the Study of Liver Diseases (AASLD)
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Algorithm for treatment initiation in HBeAg(+) chronic hepatitis
HBV DNA ≥ 20,000 IU/mL No Yes AST or ALT ≥ 2 X UNL AST or ALT 1 ~ 2 UNL ≥ Moderate necroinflammation ≥ Periportal fibrosis Yes No Treat* Observe *May wait 3-6 months for spontaneous HBeAg seroconversion. Adapted from KASL-guideline 2011
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HBeAg (-) CHB treatment
HBV -DNA ALT 치료 방침 - <2,000 IU/mL 정상 Inactive carrier- 미치료 ≥ 2,000 IU/mL 1-2배 조직검사 후 moderate- severe inflammation or periportal fibrosis 2배 이상 치료 시작 : Virological &biochemical response에 HBsAg seroconversion 생길 때까지 지속 치료 Based on practice guidelines of the American Association for the Study of Liver Diseases (AASLD)
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Algorithm for treatment initiation in HBeAg(-) chronic hepatitis
HBV DNA ≥ 2,000 IU/mL NO YES AST or ALT ≥ 2 X UNL AST or ALT 1 ~ 2 UNL ≥ Moderate necroinflammation ≥ Periportal fibrosis Treat Observe YES NO Adapted from KASL-guideline 2011
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CHB treatment in LC State HBV -DNA ALT 치료 방침 대상성 ≥ 2,000 IU/mL
> or < ULN LFT 상관 없이 치료시작 (보험 >ULN) < 2,000 IU/mL 치료를 고려함 (EASL– DNA, LFT 무관하게 치료) 비대상성 Detectable LFT 상관 없이 치료시작 Undetectable 미치료 간이식 의뢰 Based on practice guidelines of the American Association for the Study of Liver Diseases (AASLD)
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CHB treatment in compensated cirrhosis
HBV DNA ≥ 2,000 IU/mL YES NO Treat* Observe Peg-interferon may be tried in patients with well preserved liver function. Adapted from KASL-guideline 2011
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CHB treatment in decompensated cirrhosis*
HBV DNA (+) in real-time PCR YES NO Treat Observe * Consider liver transplantation. Peg-interferon is contraindicated. Adapted from KASL-guideline 2011
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Choice of regimen 주사제 interferon alfa, pegylated interferon 경구약
1차 약제 - lamivudine, entecavir 0.5mg, clevudine, telbivudine, tenofovir 2차 약제 - entecavir 1mg, adefovir, tenofovir 약제의 선택: 환자의 나이 HBeAg, HBV DNA, ALT, 간조직 소견 및 임상결과, 개인의 경제적 상태를 고려.
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PEG IFN Nucleoside analogues Administration Weekly injection Daily, orally Tolerability Poorly tolerated, intensive monitoring Well tolerated, limited monitoring Duration of therapy Finite 48 weeks >1 year, indefinite in most Maximum mean HBV DNA suppression 4.5 log10 6.9 log10 ETV Effective in high-level HBV DNA (109 IU/ml) No Yes HBeAg seroconversion During 1 year of Tx ~30% ~20% During >1 year of Tx Not applicable 30% (year 2 )– 50% (year 5) HBeAg (-) posttreatment HBV DNA supression 5 years 4 years (lamivudine) HBsAg loss 3-4% 0-3% 2 years of therapy After 1 year of therapy–HBeAg-negative 5 years 5 years Antiviral resistance None LMV: 30% year 1, 70% year 5 ADV: 0% year 1, 30% year 5 TDF: up to 4% year 1, 22% year 2 ETV: 1.2% through year 5 TBV: 0% through year 3 Cirrhosis, immunosuppressed Cost, 1 year of therapy ++++ + to ++
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Relative potency median log10 HBV DNA reduction in HBeAg(+) CHB
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Incomplete Suppression of Viral Replication Resistant Virus
Drug-susceptible virus Treatment begins Drug-resistant variant HBV replication Time Fung and Lok. Antivir Ther 2004;9:1013–26. Locarnini, et al. Antivir Ther 2004;9:679–93.
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Nucleosides Lamivudine Clevudine Telbivudine Entecavir
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Lamivudine 1st nucleoside analogue – reverse transcripase activity 억제
100mg for 48 weeks(1년 사용시) HBsAg loss : <1 HBeAg(+) HBeAg(-) HBV DNA negativity* 36% 60-89% ALT normalization 60% 60-80% HBeAg seroconversion 16-21% NA Histological improvement 50%~ 보험가 3409 * Serum HBV DBA level ≤400 copies/mL NA, not applicable Dienstag JL et al. N Engl J Med 1998;341: , Lai CL et al. N Engl J Med 1998;339:61-68, Park NH et al. Korean J,Gastroenterol 2003;42: , Lok AS et al. Gastroenterology 2003;125: , Yoon SK et al. Intervirology 2005;48:341-49, Dienstag JL et al. Gastroenterology 2003;124:105-11, Hadziyannis SJ et al. Hepatology 2000;32: , Santantonio T et al. J, Hepatol 2000;32:
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Lamivudine 내성 일차내성변이는 M204V/I 변이. L180M은 단독으로는 라미부딘 내성을 보이기 어렵지만
1st year 15-20%의 내성 발현으로 5년간 치료시 70% 에서 내성이 발생 가능 A181T/V/S 변이가 동반된 라미부딘 내성 환자: 아데포비어를 병합하여도 변이가 계속 남아 22만-37만
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Cumulative incidence of resistance(%)
투약 기간 따른 Lamivudine 내성율 80 Cumulative incidence of resistance(%) 70 65 60 53 42 40 24 20 Year1 Year2 Year3 Year4 Year5 Lai CL et al. Clin Infect Dis 2003;36: Lock AS et al. Gastroenterology 2003;125:
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Lamivudine 안전하지만 superior resistance profile 가진 약제들의 등장으로 퇴진 보험가 3409
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Clevudine 투약 중단 후에도 6개월까지 항바이러스 효과 cccDNA HBeAg(+) HBeAg(-)
HBV DNA negativity* % % ALT normalization 87% HBeAg loss % NA 보험가 7113 * Serum HBV DNA level ≤300 copies/mL NA, not applicable Yang HW et al. Korean J Intern Med 2010;25: , Lee HJ et al. Korean J Hepatol 2009;15:179192, Lau GK et al. Korean J Hepatol 2010;16:
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Clevudine M204I 변이, 보상 L220V 근무력증- 중단 후 호전 약제 내성 1년 2.3 % 2년 24.4%
금기환자 Cr clearane< 60mL/min 초치료로 권장되지 않는다 보험가 7113
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Telbivudine Cytosine analogue: 국내 2006년말 허가
Entecavir에 유사하나 좀 떨어지는 바이러스 억제능력 600 mg for 48 weeks(1년 사용시) HBeAg(+) HBV DNA 억제 6.4 log10 한도 이하 60% HBeAg(-) HBV DNA 억제 5.2 log10 한도 이하 88% ALT normalization: 77% ,74% Improved histology : 65%,67% HBeAg seroconversions : 22% by the end of year 1 30% by the end of year 2 HBsAg loss :data 없음 보험가 3409
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Good responders to LdT: (week 104)
HBeAg(+) HBeAg(-) Serum HBV DNA < 9 Log10 copies/ml and serum ALT > 2UNL at baseline Serum HBV DNA < 300 copies/ml at week 24 (71%) Serum HBV DNA < 7 Log10 copies/ml and serum ALT > 2UNL at baseline Serum HBV DNA < 300 copies/ml at week 24 (95%) Rate (%) Rate (%) 100 100 91 89 81 83 80 80 60 60 52 40 40 20 20 1.8 2.3 HBV DNA PCR(-) ALT normalization HBV DNA PCR(-) ALT normalization HBeAg SC Resistance Resistance Zeuzem S et al. J Hepatol 2009;51:11-20
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Telbivudine 내성 Resistance to telbivudine (M204I, not M204V mutations)
: less frequent than lamivudine Incidence (%) HBeAg-positive HBeAg-negative 30 25.1 20 보험가 3409 10.8 10 5 2.2 Year1 Year2
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Telbivudine 임산부 안정성 FDA Category B 부작용 거의 없고 저렴한 약 저렴해진 약가- 하루 3350원
Asymptomatic Creatine kinase elevations very low frequency of peripheral neuropathy 부작용 거의 없고 저렴한 약 저렴해진 약가- 하루 3350원 비용 대비 높은 바이러스 억제 능력 1차 약제로 잘 쓰이지도 권장되지도 않는다 보험가 3409
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Entecavir Cyclopentyl guanosine analogue polymerase inhibitor
0.5 mg for 48 weeks(1년 사용시) HBeAg(+) HBV DNA 억제 6.9 log10 한도 이하 67%(1 year) 80%(2 years) 91%(4 years) HBeAg(-) HBV DNA 억제 5.0 log10 한도 이하 90% ALT normalization: 68% ,78% Improved histology : 72%,70% HBeAg seroconversions : 21% (1 year) 31/39%(2/3 years) HBeAg loss : 22% HBsAg loss : 2%(1 year) 5%(2 years) 라미부딘, 아데포비어 100배이상 바이러스 억제능력
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HBeAg(+) undetectable HBV DNA through 5 years
Mercury no. VIHQ11PM00601 HBeAg(+) undetectable HBV DNA through 5 years 55% Year 1 83% Year 2 89% Year 3 67% 236/354 Year 4 91% 80/146 116/140 116/131 98/108 Year 5 88/94† 94% ETV-022 20 40 60 80 100 HBeAg(+) ETV long-term cohort (ETV-022→ETV-901) Proportion of patients with HBV DNA <300 copies/mL (%) Patients enrolled in ETV-901* initially received a combination of Baraclude 1.0 mg and lamivudine 100 mg daily. Subsequently, patients switched to Baraclude 1.0 mg daily. The reason that patients in 901 received the 1.0mg dose is that the blinding for the studies had not been broken at the time of entry into study Thus, patients received the 1mg dose as patients from both arms (ETV-treated and LVD-treated arms) of the initial studies (022 and 027), were enrolled, so the 1mg dose was used to cover those patients exposed to Lamivudine The grey bar shows that 67% of patients achieved undetectable HBV DNA at Week 48 among the 354 patients treated with ETV in Study ETV-022. The turquoise bars show the progressive increase in proportion of patients who achieved undetectable HBV DNA at year 1, 2, 3, 4 & 5 among the patients treated with ETV in the 5-year cohort n = * Different dosing regimen for naïve patients in the ETV-901 study † Five patients who remained on treatment at the Year 5 visit had missing PCR values (NC=M). Adapted from Chang TT et al. Hepatology 2010;51:422–30.
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Differences in mutation
adefovir 236 +/or 181 lamivuine 204 ± 180 모든 약제 반응 바이러스 LAV내성 바이러스 ADF 내성 바이러스 ETV 내성 바이러스 lamivudine 184 or 202 or 250 204 180 내성 후 바라클루드 Entecavir naive ? 라미부딘 내성 일차내성변이는 rtM204V/I 변이이다. RtL180M은 단독으로는 라미부딘 내성을 보이기 어렵지만 rtM204V/I 동반시 변이 바이러스 증식을 돕는다. 엔테카비어 변경 이후 내성은 rtL180M+ rtM204V/I 변이에 추가적으로 rtT184, rtI169, rtT188, rtS202, rtM250 등에 조합으로 나타나는데 라미부딘 내성변이와 공통되게 rtL180M+ rtM204V/I 변화 없이 발생하는 경우는 거의 없기에 엔테카비어 변경시에는 기존에 라미부딘 투약을 중단해야 하는 근거가 된다. (3) 엔테카비어 내성 치료 엔테카비어 내성 발생은 2단계 과정(two hit mechanism)을 거치는데 라미부딘 내성에서 설명한 바와 같이 tL180M+ rtM204V/I 변이가 먼저 있는 상태에서 추가적으로 rtT184, rtI169, rtS202, rtM250 등의 변이가 있을 때 발생하게 된다. 따라서 높은 유전자 장벽으로 인해 처음 치료시에는 내성 발현이 높지 않으나 라미부딘으로 치료했거나 라미부딘에 대해 이미 내성 발현 환자에서는 내성 발현이 높다. 엔테카비어 내성 환자 치료에 대한 연구결과는 아직 부족한 상태이나 초치료나 라미부딘 내성 기왕력 공히 라미부딘 내성을 가지고 있다. 엔테카비어 내성 변이는 아데포비어에 감수성을 가지고 있어 아데포비어를 추가하거나 대체하는 것을 선택할 수 있다. 엔터카비어를 유지하면서 아데포비어를 추가하는 것이 아데포비어 내성 줄이는 면에서 효율적으로 판단된다. 2007 Physician’s Desk Reference for Epivir-HBV®, Hepsera®, Baraclude®
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Cumulative Probability (%) resistance identified
ETV resistance (naïve through 6 years) 1 N=663 2 N=278 3 N=149 4 N=120 Cumulative Probability (%) ETVr = LVDr (M204V ± L180M) + T184, S202 and/or M250 substitutions 5 10 15 0.2 0.5 1.2 Years N=108 6 N=99 No new cases of resistance identified in years 4, 5 or 6 Therefore, with this high genetic barrier to resistance, Baraclude’s long-term resistance in NA naïve patients at Year 6 is only at 1.2%. No new cases of resistance were identified from Year 3 onwards. Your patients can feel confident in their treatment. They need not worry that their treatment might not work in the future. Adapted from Tenney DJ, et al. 44th Annual EASL Meeting; 22–26 April 2009;. Oral presentation.
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Entecavir 라미부딘 내성 환자에서는 하루 1mg (48주)
HBeAg(+) HBV DNA 억제 5.1 log10 한도 이하 72% ALT normalization: 61% HBeAg seroconversions : 8% HBeAg loss : 10% Lamivudine 경험자에 사용시 내성 발생율 높다 7%(1 year) 43%(4 year) adefovir or tenofovir 보험가
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Entecavir 이전에 항바이러스제제 치료를 받지 않았던 환자에서 효과가 우수하며 내성 발현율이 매우 낮다.
1.2%(5 years) 1차 약제로서 안전하고 강점 많다 보험가
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Nucleotides Adefovir (ADV) Tenoforvir (TDF)
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Adefovir Acyclic nucleotide analogue adefovir dipivoxil
야생형과 라미부딘 내성 바이러스 모두에 사용 효과가 강력하지는 않다. 단점 : 약한 항바이러스 효과 신독성 유발 가능 – creatinine monotoring lamivudine 사용 후 HBV DNA(-)가 음전화(혈청 HBV DNA ≤ 105 copies/mL 보험가 7560 비보험 병행시 12000원 이상
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Adefovir 10mg for 48 weeks(1년 사용시)
HBeAg(+) HBV DNA 억제 log10 한도 이하 13-21% HBeAg(-) HBV DNA 억제 log10 한도 이하 48-77% ALT normalization: 48-61%, 48-77% Improved histology : 53-68%, 64% HBeAg seroconversions : 12% 43% (3 years) HBeAg loss : 23% HBsAg loss : 5%(5 years) lamivudine 사용 후 HBV DNA(-)가 음전화(혈청 HBV DNA ≤ 105 copies/mL 보험가 7560 비보험 병행시 12000원 이상
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Week 24-52 Viral Decline in Patients With HBV DNA 3 log10 copies/mL
78% patients receiving ADV had serum HBV DNA ≥ 3 log10 copies/mL at Week 24 5.0 ADV 4.8 ∆ from Week 24 4.7 -0.8 log10 4.5 Potential rationale for changing regimen at Week 24 if HBV DNA is 3-4 log10 copies/mL 4.0 HBV DNA (mean log10) 4.0 ADV to LdT 3.5 3.3 ADV, adefovir; LdT, telbivudine. Telbivudine was associated with a greater degree of viral suppression than adefovir, with a mean HBV DNA of 3.3 log at Week 24 compared with 4.7 or 4.8 in the 2 adefovir arms. Of interest in the context of our present discussion is that 78% of the patients taking adefovir still had HBV DNA levels above 1000 copies/mL at Week 24. When treatment was continued to Week 52 on adefovir the mean additional log drop in HBV DNA was only 0.8, shown on the right side of the slide. Presumably, only a small percentage of these patients became HBV DNA negative by Week 52. Since complete viral suppression is the optimal endpoint of therapy, one can therefore make an argument that patients taking adefovir with HBV DNA approaching 104 copies/mL or 2000 IU/mL can—and perhaps even should—have their regimens altered at this point, rather than waiting until the end of Year 1. Even though the risk of resistance at that point is very low, the likelihood of attainment of an optimal viral response is also low, and so one might make a change in the regimen to improve the patient’s chances of complete viral suppression. 3.0 3.0 LdT -1.7 log10 3.0 24 28 32 36 40 44 48 52 Study Week Chan HL, et al. Ann Intern Med. 2007;147:
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Adefovir 내성 아데포비어를 초치료로 사용할 경우 : 낮은 내성발생을
none(1 year) 29% (5 years, HBeAg(-)) 우리나라 라미부딘 내성 이후 사용 이 경우 단독 사용 내성 높아 : 6.5%(1 year) 25% (2 years) rtN236T rtA181V/T N236T와 rtA181V/T+P237H,N238T/D 1차 약제와 라미부딘 내성 모두에 tenofovir에 자리 내 줘
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Tenofovir (Tenofovir disoproxil fumarate)
Acyclic nucleotide analogue Potent antiretroviral agent used to treat HIV infection Similar to adefovir but more potent Highly active :wild-type and lamivudine-resistant HBV 300 mg for 48 weeks(1년 사용시) HBeAg (+) HBV DNA 억제 6.2 log10 <400copies/mL 76% HBeAg (-) HBV DNA 억제 4.6 log10 <400copies/mL 93% ALT normalization: 68% ,76% Improved histology : 74%,72% HBeAg seroconversions : 21% by the end of year 1 27% by the end of year 2 HBsAg loss :3% (year 1) and 6% (year 2) 보험가 7113
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Viral suppression (<400 copies/mL) in HBeAg(-)
Proportion (95% CI) of patients with HBV DNA <400 copies/mL (69 IU/mL) by visit (long-term evaluation [LTE-TDF], missing/ addition of FTC = failure) Week 240: TDF-TDF 83% ADV-TDF 84% Overall: 83% On treatment analysis (missing = excluded); TDF-TDF = 99%, ADV-TDF = 99% Marcellin et al AASLD, Poster 1375
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Viral suppression (<400 copies/mL) in HBeAg(+)
Proportion (95% CI) of patients with HBV DNA <400 copies/mL (69 IU/mL) by visit (long-term evaluation [LTE-TDF], missing/ addition of FTC = failure) Week 240: TDF-TDF 64% ADV-TDF 67% Overall: 65% On treatment analysis (missing = excluded); TDF-TDF = 96%, ADV-TDF = 100% Marcellin et al AASLD, Poster 1375
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HBeAg Loss and Seroconversion (Study 103)
49% 40% % Patients LTE-TDF analysis: 38% e loss , 30% e seroconversion Shown here are rates of HBeAg loss (green bars) and seroconversion (orange bars) over the course of the study. Rates were calculated based on observed (Missing = excluded, FTC added included). At Week 240 the overall % of eAg loss was 49% (50% for the TDF-TDF arm and 48% for the ADV-TDF arm). Study Week For Training Purposes Only - Gilead Confidential 48
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Studies 102 & 103 Serum Creatinine Over Time
‡ Studies 102 & 103 Serum Creatinine Over Time 0.94 mg/dL 0.92 mg/dL • TDF-TDF • ADV-TDF Open-Label TDF 0.91mg/dL 0.90 mg/dL Randomized Double-Blind HBeAg-Negative HBeAg-Positive 0.87 mg/dL 0.88 mg/dL 0.86 mg/dL Week Mean (95% CI) Creatinine mg/dL Marcellin P, et al., AASLD 2010; Poster #476; Heathcote E-J, et al., AASLD 2010; Poster #477. For Training Purposes Only - Gilead Confidential 49
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LAM-experienced 96 weeks HBV DNA < 400 copies/mL
‡ LAM-experienced 96 weeks HBV DNA < 400 copies/mL 92% 84% P=0.200 Percentage (%) On treatment 98% 95% P=0.709 ~89% Patient Retention BACKGROUND Through 96 weeks, patient retention is 89%. Both an ITT analysis as well as an on-treatment analysis are presented here. MAIN MESSAGE Patients with prior lamivudine therapy were just as likely to achieve HBV DNA < 400 copies/mL as were those naïve to treatment. The on-treatment analysis shows almost completely successful virologic suppression with 95-98% < 400 copies/mL. TRANSITION Let’s look at biochemical response. Weeks on Study LAM experienced N= LAM naive N= Manns M, et al., EASL 2009; Poster #923 For Training Purposes Only - Gilead Confidential
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Summary of Resistance Analyses of Patients Originally Randomized to TDF Through Year 5
450 400 426 389 (91%) 350 364 (85%) 348 (82%) 323 (76%) 300 Total Number of Patients 250 Number of Subjects Patients with Viremia 200 Patients with Confirmed Resistance 150 100 39 (9%) 50 24 (6%) 13* (3%) 10* (3%) 9* (3%) Year 1 2 3 4 5
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Tenofovir (Tenofovir disoproxil fumarate)
The safety : 경미한 신독성과 경도의 골농도 감소 Resistance profile :5년 data (0%) Adefovir 대체 : 1차 약제로 쓰거나 Add-on therapy for lamivudine resistant 2012년 하반기부터 1, 2차 약제 모두 사용 보험가 7113
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Interferon Interferon alfa Peginterferon alfa
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Interferon alpha B형 간염 치료 최초 약제
16주- 10 million U x주 3회 or 5 million U x매일 HBeAg loss 30%, seroconversion 20%, HBsAg loss 8% undetectabl HBV DNA 13-21% Relapse rate 낮다 HBeAg(-) CHB 결과 실망 Supressed HBV DNA and LFT <20% 부작용 더 이상 사용 안 해- Standard IFN Long acting PEG IFN
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Pegylated IFN 약제 내성 바이러스 유발(-) 원래 C형간염 치료, 일주일에 한 번으로 용이해짐
치료기간이 정해짐 주 (우리보험 HBeAg(+) 24주만) HBeAg loss 30%, seroconversion 22-27% undetectable HBV DNA 10-25% mean HBV DNA reduction : 2 log10(α-2b), 4.5 log 10(α-2a) 치료 종료 6개월 뒤 HBeAg loss 35%, seroconversion 30% undetectable HBV DNA 7-14% mean HBV DNA reduction : 2-2.4log 10 보험 : ① 만 단위를 주 3회 6개월간 ② 만 단위를 매일 4개월 ③ 1000만 단위를 주3회 4개월 보험 : 대상기능상실 간질환(Hepatic decompensation)은 제외하며 단독요법으로 HBeAg(+)는 24주, HBeAg(-)는 48주를 투여한다 (휴약기간은 제외)
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Pegylated IFN HBeAg(-) (우리보험 HBeAg(+) 48주) IFN α-2a HBsAg 4%
undetectable HBV DNA 63% mean HBV DNA reduction : 4.1 log 10(α-2a) 치료 종료 5년 뒤 HBsAg loss 12%까지 점차 증가, seroconversion 30% HBV DNA suppression(<400 copies/mL) 17%까지 유지 mean HBV DNA reduction : 2-2.4log 10 보험 : ① 만 단위를 주 3회 6개월간 ② 만 단위를 매일 4개월 ③ 1000만 단위를 주3회 4개월 보험 : 대상기능상실 간질환(Hepatic decompensation)은 제외하며 단독요법으로 HBeAg(+)는 24주, HBeAg(-)는 48주를 투여한다 (휴약기간은 제외)
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Viral supression HBeAg(-) HBeAg(+) Follow-up Treatment 8 7 6 5 4 3 2 1
12 18 24 30 36 42 48 52 60 72 56 64 68 Follow-up Treatment Mean HBV DNA (10g copies/ml) Baseline Mean HBV DNA (10g copies/ml) 11 9 8 7 6 5 4 3 2 1 10 12 18 24 30 36 42 48 52 60 72 Peginterferon alfa-2a plus placebo Lamivudine Peginterferon alfa-2a plus lamivudine Follow-up Treatment Peginterferon alfa-2a plus placebo Lamivudine Peginterferon alfa-2a plus lamivudine Lau GKK, et al. N Engl J Med. 2005;352:
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Seroconversion 32 44 27 43 19 29 HBeAg(+) HBeAg(-) 80 40 60 30 40 20
Peginterferon Alfa-2a plus Placebo Alfa-2a plus Lamivudine Lamivudine P=0.007 P=0.849 Virologic Response(%) N=177 N=179 N=181 P=0.003 32 27 19 40 30 20 10 Peginterferon Alfa-2a plus Placebo (n-271) Alfa-2a plus Lamivudine (n-271) Lamivudine (n-272) P<0.001 P=0.23 P=0.002 HBeAg Seroconversion Rate(%) Marcellin P, et al. N Engl J Med. 2004;351:
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Pegylated interferon 1st line therapy 치료 종료 6개월 후 지속 반응 가임기 여성
HBsAg 혈청 소실 기대 우리나라 만성B형 간염 대부분이 유전자형이 C형: 낮은 치료 효과와 치료 반응유지 60 HBV genotype 50 40 30 20 10 A (n=90) B (n=23) C (n=39) D (n=103)
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Pegylated interferon 비싸고 부작용 (++) 종합병원 매주 9만원 월 35-36만원 주사 싫어
flu-like symptom, marrow suprression, emotion lability (irritability, anxiety, depression), autoimmune disease(특히 갑상선), alopecia, numbness and tingling(말초), diarrhea 비대상성 간경변 환자에 사용 금지 보험 : ① 만 단위를 주 3회 6개월간 ② 만 단위를 매일 4개월 ③ 1000만 단위를 주3회 4개월 보험 : 대상기능상실 간질환(Hepatic decompensation)은 제외하며 단독요법으로 HBeAg(+)는 24주, HBeAg(-)는 48주를 투여한다 (휴약기간은 제외)
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THE BATTLE AGAINST CHRONIC HEPATITIS B
Antiviral agents THE BATTLE AGAINST CHRONIC HEPATITIS B
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Mean HBV DNA reduction : after 1 year of treatment
(24 weeks) LAM1 100mg/day ADV2,3 10mg/day ETV4,5 0.5mg/day CLV6,7 30mg/day LdT1 600mg/day TDF8 300mg/day HBeAg (+) HBeAg (-) HBeAg (+) HBeAg (-) HBeAg (+) HBeAg (-) HBeAg (+) HBeAg (-) HBeAg (+) HBeAg (-) HBeAg (+) HBeAg (-) -2 -2 -2 -2 -2 -2 HBV DNA reduction (log10 copies/mL) -4 HBV DNA reduction (log10 copies/mL) -4 3.6 HBV DNA reduction (log10 copies/mL) HBV DNA reduction (log10 copies/mL) HBV DNA reduction (log10 copies/mL) -4 -4 -4 HBV DNA reduction (log10 copies/mL) -4 3.9 (median) 4.4 4.3 4.6 -6 5.0 5.1 5.2 5.5 -6 -6 -6 -6 -6 6.4 6.2 -8 -8 6.9 -8 -8 -8 -8 Mean BL viral load (log10copies/mL) 9.5 7.7 HBV DNA negativity (<300 copies/mL) 60% 88% No. pts (N) 458 222 Mean BL viral load (log10 copies/mL) 8.6 6.9 HBV DNA negativity (<400 copies/mL) 76% 93% No. pts (N) 176 250 Mean BL viral load (log10 copies/mL) 9.5 7.4 HBV DNA negativity (<300 copies/mL) 40% 71% No. pts (N) 463 224 Mean BL viral load (log10copies/mL) 8.3 6.9 HBV DNA negativity (<400 copies/mL) 21% 51% No. pts (N) 171 123 Mean BL viral load (log10copies/mL) 9.6 7.6 HBV DNA negativity (<300 copies/mL) 67% 90% No. pts (N) 354 325 Mean BL viral load (log10copies/mL) 8.3 6.9 HBV DNA negativity (<300 copies/mL) 59% 92% No. pts (N) 182 63 Not Head-to-Head Trials Adapted from: 1. Lai C-L, et al. N Engl J Med 2007;357:2576–88; 2. Marcellin P, et al. N Engl J Med 2003;348:808–16; 3. Hadziyannis SJ, et al. N Engl J Med 2003;348:800–7; 4. Chang T-T, et al. N Engl J Med 2006;354:1001–10; 5. Lai CL, et al. N Engl J Med 2006;354:1011–20; 6. Yoo BC, et al. Hepatology 2007;45:1172-8; 7. Yoo BC, et al. Hepatology 2007;46:1041-8; 8. Marcellin P et al. N Engl J Med 2008;359:2442–55.
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Long-term Viral Suppression : HBeAg(+) Undetectable HBV DNA
Lamivudine1,2 Adefovir3,4 Entecavir5–7 Clevudine8 Telbivudine1,2 Tenofovir9-11 <300 copies/mL <400 copies/mL (1yr) <1000 copies/mL (3~5yr) <300 copies/mL <300 copies/mL <300 copies/mL <400 copies/mL 100 94 96 96 93 80 89 91 80 78 Patients achieving undetectable HBV DNA (%) 76 60 67 59 60 56 40 40 39 39 36 38 20 21 N/A * * 4* 5* * 3** 4** 5** * † 2† 3‡ ‡ 5 ‡ Treatment duration (years) *Cumulative confirmed analysis; **from HBeAg(+) ETV long-term cohort (pts with available samples) †Modified Intention-to-Treat(ITT) analysis; ‡On-Treatment analysis (Missing=Excluded) Not Head-to-Head Trials Adapted from: 1. Lai CL, et al. N Engl J Med 2007;357:2576–88; 2. Liaw, et al. Gastroenterol 2009;136:486-95; 3. Marcellin, et al. N Engl J Med 2003;348:808–16; 4. Marcellin, et al. Hepatology 2008;45:750-8; 5.Chang, et al. N Eng J Med 2006;354: ; 6. Gish, et al, Gastroenterol 2007;133: ; 7. Chang, et al. Hepatology 2010;51:422-30; 8. Yoo BC, et al. Hepatology 2007;45:1172-8; 9. Marcellin, et al. N Engl J Med 2008;359:2442–55; 10. Heathcote, et al. Hepatology 2008;48(s1):376A; 11. Marcellin, et al. Hepatology 2011;52(s1):Oral presentation 028.
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Long-term Viral Suppression : HBeAg(-) Undetectable HBV DNA
Lamivudine1,2 Adefovir3,4 Entecavir5,6 Clevudine7 Telbivudine1,2 Tenofovir8-10 <300 copies/mL <1000 copies/mL <300 copies/mL <300 copies/mL <300 copies/mL <400 copies/mL 100 98 99 99 99 96 92 93 91 80 90 88 82 Patients achieving undetectable HBV DNA (%) 72 60 67 57 51 40 20 N/A N/A N/A * * * 3** * † 2† 3‡ ‡ 5 ‡ Treatment duration (years) *Cumulative confirmed analysis; **from HBeAg(+) ETV long-term cohort (pts with available samples) †Modified Intention-to-Treat(ITT) analysis; ‡On-Treatment analysis (Missing=Excluded) Not Head-to-Head Trials: Different Patient Populations and Trial Designs Adapted from: 1. Lai CL, et al. N Engl J Med 2007;357:2576–88; 2. Liaw, et al. Gastroenterol 2009;136:486-95; 3. Hadziyannis, et al. N Engl J Med 2003;348:800–7; 4. Hadziyannis, et al. Gastroenterol 2006;131: ; 5.Lai, et al. N Eng J Med 2006;354: ; 6. Shouval D, et al. J Hepatol 2006; 44(s2):S21-2; 7. Yoo BC, et al. Hepatology 2007;46:1041-8; 8. Marcellin, et al. N Engl J Med 2008;359:2442–55; 10. Heathcote, et al. Hepatology 2008;48(s1):376A; 11. Marcellin, et al. Hepatology 2011;52(s1):Oral presentation 028.
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HBeAg Seroconversion HBeAg(+) patients
Lamivudine1 Adefovir2,3 Entecavir4–7 Clevudine8 Telbivudine9,10 Tenofovir11-15 PegIFN α-2a16 24wk Treatment + 24wk post-tx f/u 100 80 Patients (%) 60 47 50 48 40 40 41 41 39 40 29 31 30 31 30 20 27 26 22 23 21 21 12 N/A N/A N/A 10 * 3** 4** 5** † 2* 3‡ ‡ 5 ‡ End of FU(Wk 72) Treatment duration (years) *Cumulative confirmed analysis; **from HBeAg(+) ETV long-term cohort (pts with available samples) †Modified Intention-to-Treat(ITT) analysis; ‡On-Treatment analysis (Missing=Excluded) Not Head-to-Head Trials: Different Patient Populations and Trial Designs Adapted from: 1. Chang, et al. J Gastroenterol Hepatol 2004;19: ; 2. Marcellin, et al. N Engl J Med 2003;348:808–16; 3. Marcellin, et al. Hepatology 2008;45:750-8; 4. Gish, et al. Gastroenterol 2007;133: ; 5. Chang, et al. Hepatology 2006;44(4s1):229A; 6. Han, et al. Hepatology 2007;46(s1):654A; 7. Han, et al. Hepatology 2008;48(s1):705A-706A; 8. Yoo BC, et al. Hepatology 2007;45:1172-8; 9. Lai CL, et al. N Engl J Med 2007;357:2576–88; 10. Liaw, et al. Gastroenterol 2009;136:486-95; 11. Marcellin, et al. N Engl J Med 2008;359:2442–55; 12. Heathcote, et al. Hepatology 2008;48(s1):376A; 13. Heathcote, et al. Gastroenterol 2011;140:132-43; 14. Heathcote,e t al. Hepatology 2010;52(s1):556A; 15. Marcellin, et al. Hepatology 2011;52(s1):Oral presentation 028; 16. Lau, et al. N Engl J Med 2005;352:
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HBsAg Loss during Continued Treatment
Lamivudine1 Adefovir2,3 Entecavir4–6 Clevudine7 Telbivudine8,9 Tenofovir10-15 PegIFN α-2a16 24wk Treatment + 24wk post-tx f/u * ** ** 2** 3** 4** 5** End of FU(Wk 72) 5 10 15 20 2 1.3 3 11 6 8 N/A Patients (%) <1 Not Head-to-Head Trials: Different Patient Populations and Trial Designs 12 5th *Cumulative confirmed analysis; **Kaplan-Meier estimates Treatment duration (years) ETV HBsAg loss6: (3 /18pts in Genotype B/C): TDF Asian Subset15: (No HBsAg loss in Genotype C) : 1. Chang, et al. J Gastroenterol Hepatol 2004;19: ; 2. Marcellin, et al. N Engl J Med 2003;348:808–16; 3. Marcellin, et al. Hepatology 2008;45:750-8; 4. Chang, et al. N Eng J Med 2006;354: ; 5. Gish, et al. Gastroenterol 2007;133: ; 6. Gish, et al. J Viral Hepat 2010;17:16-22; 7. Yoo BC, et al. Hepatology 2007;45:1172-8; 8. Lai CL, et al. N Engl J Med 2007;357:2576–88; 9. Liaw, et al. Gastroenterol 2009;136:486-95; 10. Marcellin, et al. N Engl J Med 2008;359:2442–55; Heathcote, et al. Hepatology 2008;48(s1):376A; 12. Heathcote, et al. Gastroenterol 2011;140:132-43; 13. Heathcote,e t al. Hepatology 2010;52(s1):556A; 14. Marcellin, et al. Hepatology 2011;52(s1):Oral presentation 028; 15. Gane, et al. Hepatology 2011;52(s1):Poster presentation 1429; Lau, et al. N Engl J Med 2005;352:
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High genetic barrier to resistance = Minimal Resistance
Resistance rates through 6 years among nucleos(t)ide-naïve patients Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 72 Weeks LVD1,7 23% 46% 55% 71% 80% – LdT†2,3 5% 25% – – – – ADV‡1,7 0% 3% 11% 18% 29% – TDF§4,7 0% 0%§ 0%§ 0%§ 0%§ – Speaker notes: This part of the presentation should be an explanation of why you should stop the usage of other drugs (LVD, LdT and ADV): Resistance development Compromise of your patients because you develop some mutations that can compromise the usage of ETV and TDF. TDF allowed intensification with emtricitabine to Truvada in case of HBV DNA > 400 after week 72. ETV*5–7 <1% <1% 1.2% 1.2% 1.2% 1.2% § Patients with HBV DNA ≥400 copies/mL at Week 72 could add FTC to TDF at the discretion of the investigator; 6% (38/641) were switched by Week 192.4 * Cumulative probabilities of resistance taken; † Naïve HBeAg (+); ‡ Naïve HBeAg(–); N/A not available. 1. Locarnini S. Hepatol Int. 2008;2:147– Lai CL, et al. N Engl J Med 2007;357:2576– Liaw YF, et al. Gastroenterology. 2009;136:486– Snow-Lampart A. et al. 61st AASLD Poster [Accessed Jan. 2011] Baraclude® (entecavir) SmPC, August Tenney, DJM, et al. EASL Oral Zoulim F & Locarnini S. Gastroenterology. 2009;137:1593–608.
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Comparison of Genotypic Resistance Incidence
Antiviral drug Resistance at year of therapy (% of patients) Lamivudine 23 46 55 71 80 Adefovir (naive) 3 11 18 29 Adefovir (LAM resistant) 6.5 25 35 52 65 Telbivudine 5 22 Clevudine 2.3 24.4 Tenofovir Entecavir (naive) <1 1 1.2 Entecavir (LAM resistant) 7 16 43 51
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Resistance substitution1
Cross-Resistance profile: Cross-resistance may limit treatment efficacy within drug classes In addition to cross-resistance, a recent, yet controversial Locarnini study has shown that TDF resistance could be developed through a double mutation ( ) Resistance substitution1 LVD/LdT-resistant (L180M + M204V/I) ADV-resistant (N236T) (A181T/V) Baraclude-resistant (L180M + M204V/I +/- T184G +/- S202I/G +/- M250V)* Mutation confers some degree of reduced sensitivity to listed drugs† Drugs remaining fully active Lamivudine Entecavir Lamivudine Tenofovir Telbivudine Telbivudine Telbivudine Tenofovir Entecavir Adefovir Adefovir Speaker’s Notes: TDF preferred for LAM resistant patients as ETV shows limited activity ETV preferred for ADV resistant patients as TDF shows limited activity - Study 111: ADV+ETV combination therapy for LAM resistant patients Lamivudine Entecavir Tenofovir Tenofovir Telbivudine Resistant Intermediate Sensitive † Impact on sensitivity variable; results according to laboratory analyses, not patient studies. * Represents two pathways (i) L180M+M204V/I+/-I169T+/-V173L+/-M250V and (ii) L180M+M204V/I+/-T184G+/-S202I/G 1. Adapted from Zoulim F and Locarnini S. Gastroenterology. 2009;137:1593–608.
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Patients with LAM-resistant mutations : ETV response
* HBV DNA <80 IU/mL Reijinders JG, et al. J Hepatol 2010;52:
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Patients with ADV-resistant mutations TDF
6 12 18 24 30 Months Probability of HBV DNA <400 copies/mL 0.0 0.2 0.4 0.6 0.8 1.0 p<0.0001 p<0.07 * HBV DNA <400 copies/mL Speaker’s notes: - Underlines the ADV-resistance point of previous slide ADV resistance, HBV DNA >107 at BL resistance (n=15) ADV resistance, HBV DNA <107 at BL resistance (n=6) ADV resistance (all) (n=21) ADV experienced, no ADV resistance (n=89) 21 15 3 6 3 15 12 3 89 35 Adapted from van Bömmel F et al. Hepatology 2010;51:73–80.
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Genetic barrier to resistance: Mutations required for resistance
Wild-type virus LAM1,2 rtM204V/I ± rtL180M LAM-resistant virus LdT-resistant virus ADV-resistant virus LdT1,3,4 rtM204I ± rtA181T/V ± rtM204V/rtL180 Baraclude-resistant virus ADV1,5 rtN236T +/or rtA181V No resistance reported to date, but treatment intensified at 72 weeks No HBV mutations associated with TDF resistance have been identified TDF6 ? Barrier to resistance rtT184 or rtS202 or rtM250 rtM204V/I rtL180M ETV1,7 +/– 1. Locarnini S, et al. J Hepatol. 2006;44:422– Zeffix® (lamivudine) SmPC July Sebivo® (telbivudine) SmPC September Zoulim F & Locarnini S. Gastroenterology. 2009;137:1593– Hepsera® (adefovir) SmPC June Snow-Lampart A. et al. 61st AASLD Poster [Accessed Jan. 2011]. 7. Baraclude® (entecavir) SmPC August 2010.
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In vitro Cross-resistance of HBV mutants
LAM CLV TBV ETV ADV TDF rt/M204I H I L rtL180M+rtM204V rtA181T/V rtN236T ±rt169T±rtM250V rtL180M+rtM204V ± rtT184G ±RTs202I/G rtA194T NA H : high level of resistance I : Intermediate level of resistance L : low level of resistance
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Safety & Tolerability Vertigo Gastrointestinal Headache Malaise
Dyspnoea Rash Thrombocytopenia Lactic acidosis Hypophosphatemia Impaired CrCl Tubular necrosis Pancreatitis Augmented CPK Myalgia, rhabdomyolysis Peripheral neuropathy Augmented amylase and lipase Entecavir Telbivudine Lamivudine Adefovir ETV는 두통 및 권대감등이 매우 일반적인 부작용인 반면에 텔비부딘은 CPK, 아데포비어는 권태감 그리고 테노포비어는 저인산염혈증이 빈번하게 발생되었다. Vertigo 현기증, Malaise 권태감, Hypophosphatemia 저인산염혈증, Dsypnoea 호흡곤란, Augmented CPK CPK 증가 Tenofovir Very common: 1/10 Common: 1/100-1/1,000 Rare: 1/1,000-1/10,000 Very rare: >1/10,000 Expert Panel Italian Guidelines STI review 2009;2:14-27.
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Safety Profiles Summary
Drug Renal toxicity Musculoskeletal symptoms Carcinogenicity (in animals) Teratogenicity Pregnancy Category Lamivudine - C Adefovir Entecavir Clevudine Telbivuidne B Tenofovir Fontana RJ. Hepatology 2009;49:S185-S195; Product labeling; AASLD guidelines 2009; EASL guidelines 2009; KASL guidelines 2011; APASL guidelines 2012
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Treatment Options for CHB
Drug Name Approval for CHB Guidelines Recommendations (Preferred) for 1st line monotherapies 성분명 제품명 US Korea AASLD 2009 EASL 2009 KASL 2011 APASL 2012 Lamivudine ZEFFIX® 1998 1999 Adefovir dipivoxil HEPSERA™ 2002 2004 Peginterferon-alfa PEGASYS® PEGINTRON® 2005 Entecavir BARACLUDE® 2007 Clevudine LEVOVIR® - Telbivudine SEBIVO® 2006 Tenofovir disoproxil fumarate VIREAD® 2008 (Not yet) Lok AS & McMahon BJ. Hepatology 2009;50. ,EASL. J Hepatol 2009;50: 대한간학회 만성B형간염 진료 가이드 라인 2011.
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Rescue Therapy Recommendation
Resistance Rescue Therapy Lamivudine Add ADV (A1) Add tenofovir (TDF) (B1) Stop LAM, switch to ADV or TDF plus other nucleoside analogues(C1) Switch to TDF (B2) Stop LAM, consider to switch with Peg IFN (B2) Adefovir With prior LAM resistance, - Stop ADV, switch to TDF plus other nucleoside analogues (B1) - Add ETV 1mg (B2) Entecavir Add nucleotide analogue (B1) Telbivudine Clevudine Same treatment as lamivudine (C1) Multidrug-resistance* TDF plus ETV 1mg (B1) ADV plus ETV 1mg (B2) * 다른 계열의 두 가지 이상 약제에 대한 내성 변이를 동시에 나타내는 것 (Concurrent emergence of two or more signature genotypic resistance in different classes) KASL guideline, 2011
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감사합니다. ETV TDF
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