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1 Optimal Treatment of HCV in Various Situations 전남의대소화기내과 최성규

2 내용 급성 C형간염의치료 간경변증환자의치료 간이식후치료 콩팥병환자의치료 HIV 중복감염 HBV 중복감염 정맥주사약물남용자 노년환자의치료 2013 KASL C형간염진료가이드라인페그인터페론알파 / 리바비린 2014 EASL guideline PI (TVR, BOC) based triple therapy 2014 AASLD guideline Sofosbuvir based therapy 2014 EASL postgraduate course & abstracts

3 급성 C 형간염의치료 진단 : anti-hcv(-)/hcv RNA(+), LFT 상승 치료시작 : 8-12주경과관찰후 치료기간 : 24주 치료제 : 페그인터페론알파단독 실패한경우 : PEG-IFN/RBV, PI based triple therapy (G1)

4 A: 55명증상 + 바로 PegIFN 24주 B: 52명증상 + 12주후 HCV RNA(+) (22명) PegIFN/RBV 24주 HCV RNA(-) (20명) 4명 HCV RNA + C: 25명무증상 + 바로 PegIFN 24주 Genotype 1 : 66% Delayed treatment is effective although not of equal efficacy to immediate treatment. Deterding K, et al. Lancet Infect Dis 2013;13:497

5 8-12 주관찰기간 PEG-IFNα-2b (1.5 ug/kg) 8 주 (34 명 ), 12 주 (34 명 ), 24 주 (34 명 ) Duration of Treatment genotype RVR Kamal SM, et al. Hepatology 2006;43:923

6 만성 B 형간염치료종료후의예후 44 명 43 명 43 명 Response rate combination therapy duration Santantonio T, et al. Hepatology. 2014

7 대상성간경변환자의치료 적극적인항바이러스치료 - 철저한감시와대비 PEG-IFNα + RBV : 국내 SVR 률 1 형 : 20.8%, 2 형 : 52.6% 혈액학적부작용 : recombinant erythropoietin, G-CSF PI based triple therapy (telaprevir, boceprevir) SVR 증가 (naïve & treatment experienced G1) response guided therapy보다 48주치료 serious adverse events (platelet <100,000/mm 3, albumin<3.5 g/dl) Treatment- naïve patients with compensated cirrhosis (HCC) - same treatment without cirrhosis (IA, AASLD) (sofosbuvir based therapy) SVR 도달 간경변합병증및간세포암종발생감시

8 PI based triple therapy in GT1 cirrhosis Naïve patients OPIMIZE trial (phase 3) TVR (bid, tid) SVR12 : 51% (77% š cirrhosis) RVR 있으면 24주투여 : SVR 67.9% (86.3% š cirrhosis) SPRINT-2 (phase 3) - 4 weeks PEGIFN/RBV + BOC SVR : F4-42% (F0-F2 : 67%) CUPIC study (treatment experienced cirrhotic patients) Telaprevir Boceprevir Relapsers 74.2% 53.9% Partial responders 40% 38.3% Null responders 19.4% 0% Hezode C EASL PG course

9 Risk of severe complications and SVR12 in treatment experienced patients with compensated cirrhosis Platelet count 100,000/mm 3 Platelet count >100,000/mm 3 Albumin <35 g/l N Complications, n(%) 37 19(51.4%) 31 5(16.1%) SVR12, n(%) 10(27.0%) 9(29%) Albumin 35 g/l N Complications, n(%) 74 9(12.2%) (6.2%) SVR12, n(%) 27(38.5%) 168(54.9%) Severe adverse events : 49.9% (10.4% decompensation or severe infection, 2.2% death) Hezode C EASL PG course

10 NEUTRINO trial (phase 3) Sofosbuvir 400 mg/d + PEG(2a) 180 ug/week + weight based RBV ( mg) for 12 weeks (291 treatment naïve patients with genotype 1) SVR12 : 89% (cirrhosis : 80%, without cirrhosis : 92%) COSMOS (phase 2, genotype 1) SOF 400 mg/d + simeprevir 150 mg/d ± RBV for 12 or 24 weeks Cohort 1 : null responder to PEG/RBV (F0-2) SVR12 12 wks : 96%(26/27), 93% (š RBV, 13/14) 24 wks : 91%(19/21), 100% (š RBV, 13/13) Cohort 2 : naive or null responder (F3-4) SVR4 : naïve : 100%(12/12), 100%(7/7) (š RBV) null : 93%(14/15), 100% (7/7) (š RBV)

11 AASLD guideline (initial treatment & relapsers) GT Recommended 1 IFN eligible : SOF + PEG/RBV x 12 weeks IFN ineligible : SOF + SMV ± RBV x 12 weeks Alternative SMV 12 weeks + PEG/RBV x 24 weeks SOF + RBV x 24 weeks 2 SOF + RBV x 12 weeks none 3 SOF + RBV x 24 weeks SOF + PEG/RBV x 12 weeks 4 IFN eligible : SOF + PEG/RBV x 12 weeks IFN ineligible : SOF + RBV x 24 weeks SMV 12 wks + PEG/RBV x weeks 5-6 SOF + PEG/RBV x 12 weeks PEG/RBV x 48 weeks Not recommended G1 : TVR or BOC + PEG/RBV x 24 or 48 weeks (RGT), PEG/RBV x 48 weeks Monotherapy with PEG, RBV, or a DAA Do not treat decompensated cirrhosis with PEG or SMV G2, 3 : PEG/RBV x 24 weeks, G3 (24-48 weeks) Monotherapy with PEG, RBV, or a DAA, Any regimen with TVR, BOC, or SMV G4 : PEG/RBV 48 weeks Monotherapy with PEG, RBV, or a DAA, Any regimen with TVR, BOC

12 비대상성간경변환자의치료 비대상성간경변 (CTP B) : 경험이많은센터 페그인터페론알파 + 리바비린국내소규모성적 (10명, 유전자형 1형 8명 ) : SVR 20.0% 표준용량- 용량감소, 투약중단 (>50%) 저용량부터시작하여 2주마다증량 (Peg-INFα-2a 90 ug/wk, 2b 0.5 ug/kg/wk + 리바비린 600 mg/d) 비대상성간경변 (CTP C) : 병합요법을권고하지않는다. Decompensated cirrhosis (CTP B or C) Refer to expertised practitioner (LT center) (IC) Sofosbuvir (400 mg/d) + wt based RBV (creatinine clearance, Hb) for up to 48 weeks (IIb B, AASLD) Not recommend Any IFN based therapy (III A) Monotherapy with PEG, RBV, or a DAA (III A) Telaprevir, boceprevir, or simeprevir- based therapy (III A)

13 SOF+ RBV for up to 48 weeks 61 patients : HCV and HCC (within MILAN criteria) median MELD : 8 (6-14), CTP 7-8 (class B) 44 patients LT : 41 patients (93%) HCVRNA below LLOQ post-lt 12 weeks : 23/37 (62%) HCVRNA(-) AE : fatigue, anemia, headache Treatment discontinuation : 2 patients (3%) Curry MP, et al. 64 th Annual Meeting of AASLD, 2013 SOB +RBV for 48 weeks : cirrhosis (25 Tx, 25 observation) CTP %, CTP % RVR4 : 89%, RVR8 : 97% 1- nonresponder 3- discontinue (1 AE) AE- nausea, fatigue, dizziness Afdhal N, et al. 49 th Annual Meeting of EASL, 2014

14 Sofosbuvir/Ledipasvir fixed dose combination is safe and effective in difficult-to-treat populations G3 naive G3 naive G1 CTP B G1 prior SOF SOF/LDV SOF/LDV+RBV SOF/LDV SOF/LDV+RBV 12 wk (n=25) 12 wk (n=26) 12 wk (n=20) 12 wk (n=19) RVR 23/25(92%) 23/26(88%) 15/20(75%) 19/19(100%) ETVR 23/25(92%) 26/26(100%) 20/20(100%) 17/17(100%) SVR4 17/25(68%) 26/26(100%) 16/18(89%) 14/14(100%) SVR12 16/25(64%) 26/26(100%) Pending Pending Gane EJ, et al. 49 th Annual Meeting of EASL, 2014

15 MK-5172 and MK-8742 ± Ribavirin in HCV G1 patients with cirrhosis or previous null-response. C-WORTHY STUDY MK-5172 : NS3/4A protease inhibitor MK-8742 : NS5A replication complex inhibitor MK mg QD + MK mg QD ± wt based RBG for weeks Treatment response <25 IU/mL Cirrhosis Population TW2 (n=254) TW4 (n=245) MK5172/MK8742+RBV Yes Naive 70%(45/64) 97%(56/58) MK5172/MK8742 Yes Naïve 73%(45/61) 95%(58/61) MK5172/MK8742+RBV Yes Null-responder 68%(19/28) 100%(27/27) MK5172/MK8742 Yes Null-responder 59%(17/29) 97%(28/29) MK5172/MK8742+RBV No Null-responder 66%(23/35) 97%(33/34) MK5172/MK8742 No Null-responder 72%(27/37) 94%(34/36) Lawitz E, et al. 49 th Annual Meeting of EASL, 2014

16 Compensated cirrhosis Child-Pugh <8 (MELD<18) Genotypes 2, 3 Patients awaiting LT (HCV) Genotypes 1,4 Decompensated cirrhosis Child-Pugh 8 (MELD 18) Current therapy PEG-IFN+RBV SOF+RBV PEG-IFN+RBV (±TVR/BOC in G1) SOF +PEG/RBV SOF+SMV±RBV SMV +PEG/RBV Incoming therapy No treatment SOF + RBV ABT-450/r+ABT-267+ABT-333+RBV Asunaprevir + Daclatasvir MK MK-8742 ± RBV Sofosbuvir + Ledipasvir (±RBV) Sofosbuvir + Simeprevir (±RBV) Sofosbuvir + Daclatasvir (±RBV) Marino Z, et al 2014 EASL, PG course

17 간이식후치료 치료시작 after confirmed histological damage ( 이식후 6개월이상경과 ) significant fibrosis (F 2), portal hypertension (HVPG 6 mmhg) fibrosing cholestatic hepatitis 치료요법 PEG-IFN + RBV : SVR 30-40% discontiuation (20-38%), dose reduction (66-73%), poor tolerance, risk of rejection ~5% PI based triple therapy (TVR, BOC in G1) - SVR12 : 48-59% discontiuation (13-26%), anemia drug interaction dose adjustments of CyS, TAC IFN-free regimens : SOF, SMV, RBV

18 IFN-free regimen- Sofosbuvir based 40 patients recurrent HCV infection following LT (6 months) MELD 17, CTP 7 65%(25/40) bridging fibrosis, cirrhosis SOF 400 mg/d + RBV (600 mg/d escalating) x 24 weeks End of treatment : 100% HCVRNA (< LLOQ) SVR4 : 77% (27/35) AE : fatigue, headache, athralgia, anemia(20%) Charlton MR, et al 64 th Annual Meeting of AASLD, 2013 Sofosbuvir compassionate-use program - severe recurrent HCV infection following LT 57 SOF+RBV, 30 SOF+RBV+PEG up to 48 weeks SVR12 : 54% (SOF+RBV) 44% (SOF+RBV+PEG) 76명중 53명 (70%) - improved on Tx, 10명 (13%) stable liver disease 13명 (17%) death progression of liver disease 33% AE Forns X, et al 49 th Annual Meeting of EASL, 2014

19 AASLD guideline : post-liver transplantation Treatment-naïve patients with HCV genotype 1 SOF (400 mg/d) + SMV (150 mg/d) ± RBV (escalating dose) for weeks (IIb, C) Alternate regimen SOF (400 mg/d) + RBV (escalating dose) ± PEG-IFN for 24 weeks (IIb, C) Treatment-naïve patients with HCV genotype 2 or 3 SOF (400 mg/d) + RBV (escalating dose) for 24 weeks Not recommend Monotherapy with PEG, RBV, or a DAA (III, A) TVR, BOC based regimen (III, A) Treatment naïve patient with decompensated allograft HCV infection SOF (400 mg/d) + wt based RBV (creatinine clearance, Hb) for up to 48 weeks (I, C)

20 Patients with HCV recurrence after LT Mild progression of recurrence at one year : Liver stiffness <8.7 Kpa (no need for liver biopsy or HVPG) Severe progression of recurrence at one year : Liver stiffness 8.7 Kpa F 2 liver biopsy HVPG 6 mmhg Current therapy Longterm outcome of mild HCV after LT 5yr 10yr Graft loss 3% 10% Cirrhosis 10% 30% Follow-up/ Indivisualize therapy Gambato M, et al. 49 th Annual Meeting of EASL, 2014 ABT-450/r+ABT-267+ABT-333+RBV Simeprevir+ Daclatasvir +RBV Sofosbuvir + Ledipasvir ±RBV Compensated G1 : SOF+SMV ±RBV SOF+SMV ±PEG G2, 3 : SOF+ RBV PEG-IFN+RBV (±TVP/BOC in G1) Incoming therapy (clinical trials with DAA) Decompensated SOF+ RBV Sofosbuvir +Ledipasvir (±RBV) Sofosbuvir +Simeprevir (±RBV) Marino Z, et al EASL, PG course

21 만성콩팥병환자 prevalence of CHC in HD cohorts : % (mean 13.5%) HD patients : screened for HCV at baseline and q 6 months ALT : low or normal 경한콩팥질환 ( 사구체거름률 60 ml/min) 콩팥질환이없는경우와동일 투석전단계의콩팥기능장애 ( 사구체거름률 ml/min) 감량된페그인터페론알파 (2a 135 ug/wk, 2b 1ug/kg/wk) + 리바비린 mg/d 투석중인환자 인터페론알파 (2a, 2b 300만 unit, 주3회 ) 감량된페그인터페론알파 (2a 135 ug/wk, 2b 1ug/kg/wk) 1 st generation PIs (BOC, TVR) : high rate of anemia IFN and RBV free therapy HCV treatment before kidney transplantation

22 PEG-IFN±low dose RBV for treatment-naïve patients with HCV receiving hemodialysis PegIFN -α2a 135ug + RBV 200mg PegIFN -α2a 135ug Genotype 1 n (48weeks) SVR 64% 33% Hb <8.5 g/dl 72% 6% Withdrawal (AE) 7% 4% Genotype 2 n (24weeks) SVR 74% 44% Hb <8.5 g/dl 70% 8% Withdrawal (AE) 6% 3% Liu CH, et al. Ann Intern Med 2013;159:729 Liu CH, et al. Gut 2014 [Epub ahead of print]

23 Patients with renal impariment Sofosbuvir : hepatocyte 에서 active form, inactive metabolite renal elimination Simeprevir : liver CYP3A4 에서대사, renal clearance <1%

24 HIV 중복감염환자 모든 HIV 감염자 : HCV 항체검사 (B1) 혈중 HCV RNA 검사 : HCV 항체양성인경우음성이지만원인불명의간질환 (B1) CD4 양성림프구수 < 200 cells/ul antiretroviral therapy 치료 : 페그인터페론알파 + 체중에따른리바비린용량, 48주 SVR : 1형 14-29%, 2,3형 44-73% didanosine, stavudine, zidovudine은피할것 Acute HCV in HIV patients PEG-IFN + weight based RBV for 24 weeks (RVR+) 48 weeks (RVR-)

25 SVR for oral DAA to PEG-IFN/RGB for treatment of HCV genotype 1/HIV DAA (oral) PegIFN (SC) RBV (oral) Duration SVR (%, n / N) TVR 750 mg q 8h Alfa-2a 180 ug/wk 1000 or 1200 mg/d BOC 800 mg q 8h Alfa-2b 1.5 ug/kg/wk mg/d 48wks (TVR for initial 12wks) 48wks (BOC for 44wks) 74% (28/38) 75%(271/365) 63% (40/64) 68%(213/311) SMV 150 mg/d Alfa-2a 180 ug/wk 1000 or 1200 mg/d SOF 400 mg/d Alfa-2a 180 ug/wk 1000 or 1200 mg/d SOF 400 mg/d None 1000 or 1200 mg/d 24 or 48 wks based on RVR (SMV for initial 12wks) 79% (42/53) 12 wks (all drugs) 89% (17/19) 24 wks (all drugs) * 12 wks (G2) * 12 wks (G3) 76% (87/114) 88% (23/26) 67% (28/42) Lens S, et al. Semin Liver Dis 2014;34:58

26 Clinical trials of IFN-free, oral DAA for patients with HCV/HIV NS3/4A Protease inhibitor NS5A inhibitor NS5B nucleotide analogue polymerase inhibitor NS5B nonnucleotide analogue polymerase inhibitor Ribavirin ABT450/ ritonavir Ledipasvir Daclatasvir Sofosbuvir Sofosbuvir ABT mg/d MK-5172 MK mg/d 50 patients with G1, naïve, stable HIV SOF/LDV (400mg/90mg) for 12 weeks SVR4 : 100% Osinusi A, et al. 49 th Annual Meeting of EASL, 2014 Lens S, et al. Semin Liver Dis 2014;34:58

27 AASLD guideline : HIV/HCV coinfection G 1 : Treatment-naïve and prior PEG/RBV relapsers IFN eligible : SOF+PEG/wt based RBV x 12 wks (I B) IFN ineligible : SOF + RBV x 24 wks (I B) SOF + SMV ± RBV x 12 wks (IIa C) Treatment experienced (PEG/RBV non-responders) SOF+ SMV ± RBV x 12 wks (IIa C) G 2 : SOF + RBV x 12 wks (I B) prior non-responder, cirrhosis - 16 wks G 3 : SOF + RBV x 24 wks (I B) G 4,5,6 : same as HCV monoinfection Allowable antiretroviral therapy SOF : all except didanosine, zidovudine SMV : limited to raltegravir, rilpivirine, maraviroc, enfuvirtide, tenofovir, emtricitabine, lamivudine, abacavir

28 HBV 중복감염환자 prevalence : 5-20% in HBsAg positive patients 2-10% in HCV positive patients HBsAg/anti-HCV positive patients HCV RNA positive Inactive HBV infection profile Treat as HCV mono-infection. Monitor HBVDNA Active HBV infection Treat with IFN based anti-hcv therapy. HBV response (-) : NUC therapy sequential treatment (anti-hcv first, then anti-hbv) simultaneous treatment : drug interaction IFN telbivudine 피한다.(neuromuscular side effect) BOC : ETV, TDF, ADV, LMV no interaction TVR : TDF (30% 상승 )

29 경기인천지역 18 명 /758 명 PEG-IFN/RBV : 2.37% 1b : 8 명, 2a/c : 5 명, 2 : 3 명, 1a : 2 명 87.5% 60% Kim YJ, et al. Korean J Hepatol 2011;17:199

30 정맥주사약물남용자 HCV 항체양성률 % ( 국내 ) 20-25% of deaths among HCV patient liver disease 1a, 1b, 3a : common, 4d in Europe, 6 in Southeast Asia 메타분석 (2,800 명, 38.2% 약물남용지속 ) 페그인터페론 + 리바비린병합요법 SVR : 44.9%(1 형 ) 70.0%(2, 3 형 ) 약물남용을중단한자 : 현재의표준치료 약물남용지속자 : 환자의치료의지등을분명히평가 약물상호작용 TVR, BOC - methadone 과작용이없으나 heroin 혈중농도증가 SOF : methadone 과작용이없다

31 치료결정 Chronic Hepatitis C in the Elderly Factors favoring treatment now Few comorbidities Advanced liver fibrosis Extrahepatic manifestations of HCV Factors favoring delaying therapy Comorbidities renal impairment, anemia Minimal liver fibrosis Previous failed therapy Tolerabilty : premature treatment discontinuation, dose reduction > age 60 : 70% : dose reduction of RBV within 12 weeks 30% : stop (vs 15%) anemia, depression, fatigue, flu-like Sx Lower SVR : 46% (>over 60) vs 70% TVR : > age 65 anemia SVR : 50% (pre-cardiac tests, medication Hx) IFN-free therapy (SOF trial, 90%>age 65) no difference in efficacy and tolerability

32 요약 각환자의개별적상황을충분히고려한다. PEG-IFN/RBV에서새로운 DAA의병합요법 (IFN free regimen) 급성 C형간염 : PEG-IFN 단독으로 12주치료가능 대상성간경변 : 만성 C형간염과동일하게적극적인치료 비대상성간경변 : IFN free DAA regimen을기대 콩팥병환자 : 약제의신장배설관계파악, 신장이식전치료 HIV/HCV 중복감염 : 약물상호작용파악 HBV/HCV 중복감염 : HCV 치료우선, HBV DNA monitoring 정맥주사약물남용자 : 약물상호작용 노년층 : 다른질환여부 ( 신장기능 ), 약물상호관계 새로운 DAA 의 Cost 및 Viral resistance

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<30322E535453BABBB9AE2DC6EDC1FD2E687770> 만성 C 형간염의치료 : 주사제를포함한요법 Treatment of Chronic Hepatitis C-Interferon-Based Therapy 인제대학교일산백병원내과 김경아 With the development of direct acting antivirals (DAAs), the outcomes of hepatitis C treatment have been