만성 B 형간염진단과치료 / 박상훈 소강당 만성 B 형간염의치료 박상훈 한림의대소화기내과 B 형간염의감염경로 치료목표 수평감염 수직감염 Goals 감염원 피감염자 산모 단기 : HBV 의증식을억제하여간염을완화, 섬유화를방지 장기 : 만성 B 형간염단계에서염증을완화시켜간경변증, 간기능부전, 혹은간암으로진행을방지 소아 - 소아오염된주사바늘성적접촉보건의료종사자수혈 5 세이후감염자 : 6% 만성화 신생아 주산기감염 감염된신생아 : 9% 가만성화 End-points HBsAg 소실또는혈청전환 HBeAg 혈청전환의지속적인유지 치료종료후지속적인 불검출 : PegIFN 치료중 불검출 : NUCs Harrison 16th edition. Chapter 285. Table2 치료시기 질병진행과정및치료시점 자연경과중 tolerance clearance Control (Non-replication) Escape (Reactivation) 면역제거기 (e 항원양성만성 B 형간염 ) < HBeAg+ve >< HBeAg ve > 재활성화기 (e 항원음성만성 B 형간염 ) HBV-DNA monitor treat monitor treat HBeAg +ve chronic hepatitis Inactive (carrier) state HBeAg ve active chronic hepatitis Lok ASF, McMahon BJ. Hepatology. 29;5:1-36. 미국간학회가이드라인, 29 137
211 년대한임상건강증진학회춘계통합학술대회 치료대상 치료대상 만성 B 형간염 간경변증 HBeAg (+) HBeAg (-) Compensated Decompensated KASL (27) 2 x UNL 2, 2 x UNL 2, APASL (28) 2 x UNL 2, 2 x UNL 2, EASL (29) 1 x UNL > 2, 1 x UNL > 2, KASL (27) 1 x UNL 2, Detectable APASL (28) > 2, Detectable EASL (29) Detectable Detectable AASLD (29) > 2 x UNL > 2, > 2 x UNL > 2, AASLD (29) > 2, > 1 x UNL < 2, Detectable Cumulative Incidence of Cirrhosis according to baseline HBV-DNA Higher baseline viral loads increased rate of HCC Cumulative Incidence of Liver Cirrhosis 4 3 2 1 Baseline HVB DNA Level, Copies/mL 1. x 1 6 5 1.-9.9 x 1 1.-9.9 x 1 4 3-9.9 x 1 3 <3 1 2 3 4 5 6 7 8 9 1 11 12 13 Year of Follow-up Cumulative incidence of HCC 14 12 1 8 6 4 2 1 2 3 4 5 6 7 8 9 1 11 12 13 Year of follow-up >1 6 cpm 15 1 5 1 6 cpm 1 4 1 5 cpm 3 1 4 cpm <3 cpm 1.3 RR=11 Iloeje, Gastroenterol 26 Chen CJ et al. JAMA 26; 295 :65 73. Disease progression in patients with CHB 약제의선택 치료시유의할점 Untreated ( 215 pts ) LAM treated ( 436 pts ) Cirrhosis progression 17 7 at 32 mon. (p=.1) HCC development 7.4 3.9 at 32 mon. (p=.47) 치료제 각약제의장, 단점 각약제의치료성적 Liaw et al. N Engl J Med 24;351:1521-1531 138
만성 B 형간염진단과치료 / 박상훈 치료시유의할점 치료제 현재치료에사용되고있는항바이러스제들은모두나름대로의장단점을가지고있으며장기적치료효과에도한계가있음 치료를시작하기전에환자의연령, 간질환의중증도, 치료에대한반응가능성, 치료에따르는부작용과합병증등을고려 치료여부를신중히판단하는것이필요 Interferon-α 1992 Lamivudine(Zeffix ) 1998 Adefovir dipivoxil (Hepsera ) 22 Entecavir (Baraclude ) 25 Peg-interferon (Pegasys ) 25 Telbivudine (Sebivo ) 26 Tenofovir (Viread ) 28 Clevudine (Levovir ) 26 각약제의장, 단점 치료효과 e 항원양성만성 B 형간염 페그인터페론 일정기간치료반응지속성 좋음내성없음 e항원혈청전환률높음 장점 주사제부작용고가 단점 Control Peg IFNα 48/72 wks LMV ADV ETV LdT TDF CLV s 항원소실가능성 라미부딘 경구부작용-거의없음 높은내성률 (high) - 1년 : 2%, 5년 : 7% Loss of serum -17 25 4-44 21 67 6 76 59 장기성적보유 아데포비어엔테카비어 저가낮은내성률 (lower) - 1년 : %, 2년 : 3%, 3년 : 11%, 4년 : 18%, 5년 : 29% 강력한바이러스억제효과매우낮은내성률 (lowest) 신장독성바이러스억제-다소느림동물실험 ( 종양 ) Loss of HBeAg 6-12 3 / 34 17-32 24 22 26 11.1 HBeAg seroconversion 4-6 27 / 32 16-21 12 21 22 21 7.6-1 년 :%, 3,4,5 년 : 1.2% ( 라미부딘내성 : 1%, 11%, 27%, 41%, 43% - 5 년 ) Loss of HBsAg -1 3 1 2 3.2 텔비부딘 안전 -FDA 임신중사용가능성 : B 내성률 : 중간 (intermediate) 테노포비어 강력한바이러스억제효과강력한효과 -초치료및라미부딘내성에도효과매우낮은내성률 (lowest) 안전 FDA: B( 임신 ) -1년: 2.2-5%, 2년 : 11-25% 근육병, 말초신경병장기성적부족 Fanconi syndrome, 신기능저하골밀도저하 Normalization of Histologic improvenent 7-24 39 41-75 48 68 77 68 68.2 38 49-56 53 72 65 74 클레부딘 s항원반응 ( 소실 ): 3% 강력한효과투약중단후에도항바이러스효과지속 장기성적부족근육병 Durability of response 5-8 ~9 69 ~8 내성률 1 년 : 1.3% 치료효과 치료전략 e 항원음성만성 B 형간염 치료반응의정의 Loss of serum Normalization of Histologic improvenent Durability of response Control Peg IFNα LMV ADV ETV LdT TDF CLV -2 63 6-73 51 9 88 93 92.1 1-29 38 6-79 72 78 74 76 74.6 33 48 6-66 64 7 67 72 ~2 <1 ~5 3 On (Peg) IFN therapy On NUC therapy Primary non-response <1 log 1 IU/mL decrease <1 log 1 IU/mL decrease at 12 wks at 12 wks Virological response Partial virological response <2 (3.3 log 1 )IU/mL at 24 wks Undetectable by RT-PCR within 48 wks >1 log 1 IU/mL decrease but detectable HBV-DNA at 24 wks: LMV, LdT at 48 wks: ETV, ADV, TDF 139
211 년대한임상건강증진학회춘계통합학술대회 치료전략 치료모니터링 (Roadmap concept) 치료모니터링 (Roadmap concept) Assessment of Primary Non-Response at Week 12 Start Treatment Assess for Primary Nonresponse at Week 12 ( <1 IU/mL from Baseline) Virologic Response: 1 log IU/mL reduction from baseline Primary Treatment failure: <1 log IU/m reduction from baseline Early Predictors of Efficacy at Week 24 Compliant: Add more potent drug Non-Compliant: Counsel on adherence Complete VR (<6 IU/mL) Partial VR ( 6 to 2, IU/mL) Inadequate VR ( 2, IU/mL) Assessment of Early Predictors of Efficacy at Week 24 Keeffe EB, et al. Clin Gastroenterol Hepatol 27;5:89-7. 치료모니터링 (Roadmap concept) Complete Virologic Response: PCR negative Continue with same drug; monitor every 6 months Assessment of Early Predictors of Efficacy at Week 24 LAM/LdT: Add second drug with different genetic mutation profile Keeffe EB, et al. Clin Gastroenterol Hepatol 27;5:89-7. Partial Virologic Response: 6 to <2, IU/mL ETV/TDF monitor every 3 months; continue beyond 48 weeks Complete response at 48 weeks: continue therapy Inadequate Virologic Response: 2, IU/mL ADV: monitor every 3 months; continue until 48 weeks Add more potent drug; monitor every 3 months Incomplete response at 48 weeks: add more potent drug that is not crossresistant 치료모니터링 - partial virologic reponse of NUCs Patients with detectable by PCR, % 1% 8% 6% 4% 2% Baseline % 68% LAM 1 9.5 Week 24 29% 55% LDT 1 1) Lai C-L et al. NEJM 27;357:2576-88; 2) Marcellin P et al, NEJM 28;359:2442-55; 3) Chang T-T, et al. NEJM 26;354:11-1; 4) Lai C-L et al. NEJM 26;354:111-2. 7.4 9.5 2% 7.7 87% 8.9 ADV 2 37% 7. Week 48 33% ETV 3,4 9.6 1% HBeAg-positive HBeAg-negative 24% TDF 2 7% 7.6 8.6 6.9 Therapeutic options for partial virological response Lamivudine, clevudine, telbivudine change to entecavir or tenofovir add tenofovir Adefovir in LAM-resistant pts change to tenofovir add lamivudine Entecavir add tenofovir 14
만성 B 형간염진단과치료 / 박상훈 치료반응에따른내성 치료기간 % Resistance 1 8 6 4 2 Lamivudine Long-term resistance vs W24 viral load (median 29 month follow-up) 8 12 32 64 < 2 < 3 log < 4 log > 4 log at Week 24 N = 159 HBeAg+ % Resistance 1 8 6 4 2 4 Adefovir Resistance at W144 vs W48 viral load 26 67 < 3 log 3 6 log > 6 log at Week 48 N = 114 primarily HBeAg KASL (27) APASL (28) EASL (29) AASLD (29) HBeAg (+) HBeAg (-) e 항원소실후적어도 1 년이상 e 항원혈청전환과함께 HBV DNA 가검출되지않음이적어도 6 개월간격으로 2 번검사에서확인될때까지투여 e 항원혈청전환후 6-12 개월추가투여 e 항원혈청전환과함께 HBV DNA 가검출되지않음이확인된후적어도 6 개월이상추가투여 비증식상태가장기간유지될때까지지속적투여또는 s 항원소실때까지 적어도 6 개월간격으로 3 번검사에서 가검출되지않을때투여중지고려 장기투여 s 항원소실때까지지속적투여 Yuen, et al. Hepatology 21; 34:785 791 Locarnini S, et al. J Hepatol 25; 42(Suppl 2):17 (EASL 25. Abstract 36) 요약 초치료시 치료여부를신중히판단 내성은적고효과는강력한약제를선택 치료반응에대한지속적인추적관찰 Case 41-year-old computer technician recently learned he has CHB. He is asymptomatic. He drinks occasionally and is overweight LFTs: 72, AST 55, ALP 76 AFP: 4.5 HBeAg (+) 2.3 1 9 copies/ml Liver US showed coarse echogenicity, but the liver surface is smooth Audience voting Panel discussion What are the causes of his slightly raised? 1. CHB 2. HCV co-infection 3. NASH 4. Any of the above What are the risk factors for cirrhosis for this patient? What recommendations would you make for his management? 141
211 년대한임상건강증진학회춘계통합학술대회 Case answers Case follow-up What are the risk factors for cirrhosis for this patient? Male, older age, HBeAg (+), high, ob esity What recommendations would you make for his management? Monitor regularly or liver biopsy After 3 months, was 85 and was 3.5 1 9 copies/ml The patient s BMI was 28 Liver biopsy showed steatohepatitis with 3% fat, no lobular hepatitis, no portal h epatitis, and no fibrosis Audience voting Case follow-up Would you start antiviral therapy now? 1. Yes 2. No 3. Maybe Weight loss and exercise were recommended 6 months later: weight loss was 3 kg, was 55, was 5.5 1 9 copies/ml, and HBeAg remained positive Key learning points Marginally elevated liver function tests could b e due to NASH in HBV infected patients Liver biopsy is useful to distinguish NASH from active CHB Careful evaluation is essential before starting t herapy 142