III CURSO PARA RESIDENTES SOBRE DIAGNÓSTICO Y TRATAMIENTO DE LAS ENFERMEDADES HEPÁTICAS Barcelona, de noviembre de 2011 III CURSO PARA RESIDENTES SOBRE DIAGNÓSTICO Y TRATAMIENTO DE LAS ENFERMEDADES HEPÁTICAS Barcelona, de noviembre de 2011 Tratamiento de la hepatitis crónica C Javier García-Samaniego Unidad de Hepatología Hospital Carlos III. CIBERehd Madrid Javier García-Samaniego Unidad de Hepatología Hospital Carlos III. CIBERehd Madrid

Objetivos del tratamiento Objetivo primario = curar Eliminar el virus 1 Detener la progresión (necrosis/fibrosis) Aliviar los síntomas Objetivos secundarios Reducir la progresión de la fibrosis 1 Reducir la evolución a cirrosis 2 Evitar descompensaciones Evitar el CHC 2 1. Worman. Hepatitis C: Sourcebook Peters et al. Medscape HIV/AIDS eJournal. 2002;8(1).

Host DNA Hepatitis C differs from HIV and HBV No long-term or latent reservoir HBVHIVHCV cccDNA Proviral DNA Viral RNA TREATMENT Long-term suppression of viral replication Long-term suppression of viral replication Viral Eradication = Cure

Evolución del tratamiento de la hepatitis C Descubrimiento del genoma del VHC La combinación IFN + RBV mejora la respuesta Peg-IFN alfa más RBV terapia de referencia Tratamiento con IFN alfa 3 veces/sem durante 24 o 48 sem. Resultados pobres Desarrollo de Peg-IFN en monoterapia Terapia basada en la respuesta viral Desarrollo de nuevos antivirales

Evolución de la tasa de respuesta RVS (%) 66% 19% 41% 39% 6% sem , s 1 1. McHutchison J, et al. N Engl J Med 1998; 339: Poynard T, et al. Lancet 1998; 352: Zeuzem S, et al. N Engl J Med 2000; 343: Lindsay K, et al. Hepatology 2001; 34: Manns M, et al. Lancet 2001; 358: Fried M, et al. N Engl J Med 2002; 347: Zeuzem S, et al. J Hepatol 2005; 43: % Todos los genotipos 23% 56% Peg-IFN  -2b + RBV Peg-IFN  -2 a + RBV Peg-IFN  -2b Peg-IFN  -2a IFN  + RBV IFN 

EASL 2011 HCV Guidelines: PegIFN/RBV Regimens Craxi A, et al. J Hepatology. 2011;[Epub ahead of print]. Genotype 1/4PegIFN alfa-2aPegIFN alfa-2b PegIFN dose (weekly)180 µg1.5 µg/kg RBV dose (daily)15 mg/kg Planned duration*48 wks Genotype 2/3PegIFN alfa-2aPegIFN alfa-2b PegIFN dose (weekly)180 µg1.5 µg/kg RBV dose (daily)800 mg  If low responsiveness anticipated 15 mg/kg Planned duration † 24 wks *24 wks of therapy can be considered in patients with low HCV RNA (< 400, ,000 IU/mL) who achieve RVR. † wks can be considered in patients who achieve RVR.

Hepatitis C: escenario en 2011 Tratamiento con pegIFN + RBV en pacientes con genotipos 2, 3 y 4 Aprobación de los primeros DAAs: telaprevir y boceprevir Incremento de la RVS hasta el 75% con terapia triple en pacientes naïves G1 Problemas potenciales con el uso de estos nuevos fármacos: –Selección adecuada de los pacientes –Control y monitorización inapropiados –Manejo de los efectos adversos –Resistencias –Interacciones farmacológicas

HCV Treatment: A Lexicon of Acronyms DAAs: direct acting antivirals IL28B: IL28B polymorphism (rs ) genotype test NA: nucleoside analog polymerase inhibitors NNI: nonnucleoside polymerase inhibitors PI: protease inhibitors MV: minority variants UDPS: ultradeep pyrosequencing vBT: viral breakthrough RGT: response-guided therapy eRVR: extended rapid virological response DRM: drug-resistant mutations

New predictors: Genetic markers associated with SVR to PEG plus RBV in genotype 1 HCV patients* *Ge D, et al. Nature.2009;461: Factor Associated With SVROdds Ratio (95% CI) Baseline HCV RNA (< vs ≥ 600,000 IU/mL) IL28B rs genotype (CC vs TT) 7.3 Baseline fibrosis (METAVIR F0-F2 vs F3- F4) Whites (n = 871)Blacks (n = 191)Hispanics (n = 75)

Genetics Predict Response: IL28B C/C Associated With Higher SVR Rate in Gt 1 SVR (%) European- Americans African- Americans HispanicsCombined T/TT/CC/CT/CT/CT/CT/TC/CT/TC/CT/TC/C n = P = 1.06 x P = 2.06 x P = 4.39 x P = 1.37 x Genotype of rs on chromosome 19. Ge D et al. Nature. 2009;461:

Select DAAs in Clinical Development Phase IPhase IIPhase III Protease InhibitorsABT-450 ACH-1625 GS 9451 MK-5172 VX-985 BMS Asuprenavir CTS-1027 Danoprevir GS 9256 IDX320 Vaniprevir BI Boceprevir (approved) Telaprevir (approved) TMC435 Nonnucleoside polymerase inhibitors BI IDX375 ABT-333 ABT-072 ANA598 BMS Filibuvir Tegobuvir VX-759 VX-222 Nucleoside polymerase inhibitors IDX184 PSI-7977 RG7128-Mericitabine NS5A inhibitorsA-831 PPI-461 BMS Daclatasvir BMS CF102

Anti-HCV drugs in development

Telaprevir o Boceprevir Ribavirina PegIFN-α Standard of care en 2012

Boceprevir and Telaprevir Boceprevir, a potent inhibitor of HCV NS3/4A protease Telaprevir, a potent inhibitor of HCV NS3/4A protease Both being tested in combination with standard-of- care pegIFN alfa-2/RBV in phase III studies in chronic HCV infection Boceprevir –SPRINT-2: naive GT1 patients –RESPOND-2: nonresponder GT1 patients (partial responders and relapsers) Telaprevir –ADVANCE: naive GT1 patients –ILLUMINATE: response- guided therapy in naive GT1 paitents –REALIZE: nonresponder GT1 patients (null responders, partial responders, relapsers)

Phase III ADVANCE: Telaprevir + PegIFN/RBV in GT 1 Tx-Naïve Patients Treatment-naive patients with GT 1 HCV (N = 1088) Wk 12 TVR + PR* (n = 364) TVR + PR* (n = 363) PR* (n = 361) eRVR † : PR* Wk 72 Wk 48 Wk 8 Follow-up *TVR 750 mg q8h; pegIFN alfa-2a 180 µg/wk; weight-based RBV mg/day. † eRVR = undetectable HCV RNA at Wks 4 and 12. Jacobson I, et al. N Engl J Med 2011;364: Wk 24 PR* eRVR † : PR* PR* Follow-up  Randomized, placebo-controlled trial

ADVANCE: SVR rates SVR P< /363250/364158/361n/N = Percent of patients with SVR T12PRT8PRPR Jacobson I, et al. N Engl J Med 2011; 364:

Jacobson I et al. N Engl J Med 2011: 364: Outcome, %8-Wk TVR/PR + 16/40-Wk PR (n = 364) 12-Wk TVR/PR + 12/36-Wk PR (n = 363) 48-Wk PR (n = 361) Discontinuation of TVR/placebo due to rash 7111 Discontinuation of all drugs due to AEs874  Anemia Telaprevir: Discontinuations Discontinuations due to adverse events in Phase III ADVANCE:

N = 540 Telaprevir 750 mg q8h + Peg-IFN  2a + RBV Telaprevir Ph3 Trial: ILLUMINATE – GT1 Naïve Peg-IFN  2a + RBV eRVR Follow-up Peg-IFN  2a + RBV Follow-up Peg-IFN  2a + RBV No eRVR Weeks on therapy * eRVR = undetectable HCV RNA at week 4 and week 12 Non-inferiority trial requested by the FDA to specifically demonstrate that treating GT1 Naïve patients for 24 weeks was not a disadvantage compared to treating them for 48 weeks

ILLUMINATE: Undetectable HCV RNA over time – ITT Population 389/540352/540 n/N= RVReRVR Patients with Undetectable HCV RNA levels (%) /540 EOT /540 SVR 72 Sherman KE, et al. N Engl J Med 2011; 365: 1551.

ILLUMINATE SVR Rates - Noninferiority of 24-week Regimen  4.5% (2-sided 95% CI = -2.1% to +11.1%) Patients with SVR (%) T12PR24T12PR48 149/ /160n/N= Sherman KE, et al. N Engl J Med 2011; 365: 1551

REALIZE Telaprevir + PegIFN/RBV in GT 1 HCV Pts Who Failed Previous PegIFN/RBV * Weeks 72 T12/PR48 Peg-IFN + RBV TVR + Peg-IFN + RBV Pbo + Peg-IFN + RBV n=266 Follow-up SVR assessment TVR+ Peg-IFN + RBV Peg-IFN + RBV T12(DS)/ PR48 n=264 Follow-up Pbo + Peg-IFN + RBV *Randomization stratified by viral load and prior response; stopping rules applied for TVR (Weeks 4, 6, and 8) and Peg-IFN/RBV (Weeks 12, 24, and 36) Peg-IFN = 180μg/week; RBV 1000–1200mg/day; TVR = 750mg every 8 hours ClinicalTrials.gov identifier: NCT Pbo = placebo; DS = delayed start Pbo/PR48 ( control ) Pbo + Peg-IFN + RBV Peg-IFN + RBV n=132 Follow-up Zeuzem, et al. N Engl J Med 2011; 364:

REALIZE: SVR According to Previous Response SVR Based on Previous Response, % (n/N) T12/ PR48 LI-T12/ PR48 PR48 Relapser83* (121/145)88* (124/141)24 (16/68) Partial responder59* (29/49)54* (26/48)15 (4/27) Null responder29* (21/72)33* (25/75)5 (2/37) *P <.001 vs PR48. Zeuzem S, et al. N Engl J Med. 2011;364:

Resumen de los estudios de telaprevir El tratamiento “guiado” por la respuesta viral (RGT) durante 24 semanas es igual de eficaz que el de 48 semanas de duración en pacientes naïve con eRVR (semanas 4-12). La RGT es posible en 2/3 de los pacientes La duración óptima del tratamiento con TVR es de 12 semanas 1. Jacobson IM, McHutchison JG,Dusheiko GM, et al. AASLD 2010: Abstract Sherman KE, Flamm SL, Afdhal NH, et al. AASLD 2010:LB-2.

Telaprevir Regimens Treatment-naive patients and previous relapsers –Triple therapy with TVR 750 mg TID + pegIFN/RBV for 12 wks, followed by wks of pegIFN/RBV alone Duration of pegIFN/RBV dependent on treatment response (cirrhotics may benefit from full 48-wk course) Previous partial and null responders –Triple therapy with TVR 750 mg TID + pegIFN/RBV for 12 wks, followed by 36 wks of pegIFN/RBV alone Telaprevir [package insert] *

Week 4 Week 48 PR + Placebo Follow-up PR lead-in PR + Boceprevir Week 28 Week 72 TW 8-24 HCV-RNA Undetectable TW 8-24 HCV-RNA Detectable PR + Placebo Follow-up SPRINT 2: Study Design Control 48 P/R N = 363 BOC RGT N = 368 Peginterferon (P) administered subcutaneously at 1.5 μg/kg once weekly, plus ribavirin (R) using weight based dosing of mg/day in a divided daily dose. BOC 800 mg 3 times daily Poordad F, et al. N Engl J Med 2011; 364: PR + Boceprevir Follow-up BOC/ PR48 N = 366 PR lead-in PR lead-in

SPRINT 2: SVR and Relapse Rates (ITT) p < Non-Black Patients p = p =0.004 Black Patients SVR* Relapse Rate /14 3/ /232 18/230 *SVR was defined as undetectable HCV RNA at the end of the follow-up period. The 12-week post-treatment HCV RNA level was used if the 24-week post- treatment level was missing (as specified in the protocol). A sensitivity analysis was performed counting only patients with undetectable HCV RNA documented at 24 weeks post-treatment and the SVR rates for Arms 1, 2 and 3 in Cohort 1 were 39% (122/311), 66% (207/316) and 68% (210/311), respectively and in Cohort 2 were 21% (11/52), 42% (22/52) and 51% (28/55), respectively. Poordad et al. NEJM 2011

Boceprevir: Adverse Events and Discontinuations 1. Poordad F, et al. NEJM Anemia and dysgeusia reported more frequently in BOC arms vs control in SPRINT-2 [1-2] Outcome4-Wk PR + Response- Guided BOC/PR (n = 368) 4-Wk PR + 44-Wk BOC/PR (n = 366) 48-Wk PR (n = 363) Adverse event, %  Anemia [1] EPO use  Dysgeusia [2] Discontinuations due to adverse events, % [1] 1216  Anemia [1] 221

Week 4 Week 48 PR + Placebo Follow-up PR lead-in PR + Boceprevir PR lead-in Week 36 Week 72 TW 8 HCV-RNA Undetectable TW 8 HCV-RNA Detectable/ TW 12 Undetectable PR + placebo Follow-up RESPOND-2 Study Arms and Dosing Regimen Control 48 P/R N = 80 BOC RGT N = 162 Peginterferon ( P) administered subcutaneously at 1.5 μg/kg once weekly, plus Ribavirin (R) using weight based dosing of mg/day in a divided daily dose Boceprevir dose of 800 mg thrice daily Bacon et al. N Engl J Med 2011; 364: PR + Boceprevir PR lead-in Follow-up BOC/ PR48 N = 161 HCV-RNA measured by the Cobas TaqMan assay (Roche). Patients with detectable HCV-RNA (LLD=9.3 IU/mL) at week 12 were considered treatment failures. Week 12 futility

RESPOND-2 SVR and Relapse Rates Intention to treat population p < SVR Relapse Rate week HCV RNA level used if 24-week post-treatment level was missing. A sensitivity analysis where missing data was considered as non-responder, SVR rates for Arms 1, 2 and 3 were 21% (17/80), 58% (94/162) and 66% (106/161), respectively. SVR rates in BOC RGT and BOC/PR48 arm not statistically different (OR, 1.4; 95% CI [0.9, 2.2]) % of Patients PR 48 BOC RGT BOC/PR48

Las pautas de tratamiento con BOC requieren un periodo de 4 semanas de lead-in (LI) con PEGIFN+RBV La RGT (viremia C indetectable en las semanas 8 y 24) es posible en aproximadamente la mitad de los pacientes naïve Se requiere un mínimo de 24 semanas de BOC para la respuesta viral óptima en pacientes naïve Se requiere LI + un periodo mínimo de 32 semanas de tratamiento con BOC/PEGIFN/RBV para los pacientes con fallo a un tratamiento previo con PEGIFN/RBV 1.Poordad F, et al. NEJM 2011; 364: Bacon B et al. NEJM 2011; 364: Resumen de los estudios Sprint-2 1 y Respond-2 2

Recommended Treatment Duration With BOC in Tx- Naive Patients Boceprevir [package insert]  All patients start with pegIFN/RBV for 4 wks  At Wk 4, BOC added to pegIFN/RBV for a duration determined by response at Wks 8 and 24  Stop all therapy if HCV RNA > 100 IU/mL at Wk 12 or detectable at Wk 24 HCV RNA at Wk 8 HCV RNA at Wk 24 Recommendation Undetectable Complete BOC + pegIFN/RBV at Wk 28 DetectableUndetectable  Continue BOC + pegIFN/RBV through Wk 36, then  PegIFN/RBV through Wk 48

Similarities and Differences in Phase III Studies of TVR and BOC in GT1 Naive Pts ParameterTVR [1] BOC [2] PR lead-in?NoYes: 4 wks PegIFN alfa formulation2a2b PI dosing requirements TID; administer with fatty meal TID Duration of PI triple therapy 8-12 wks followed by wks PR wks after 4 wks PR lead-in Qualification for shortened therapy (response guided) Undetectable HCV RNA until Wk 12 of triple therapy Undetectable HCV RNA until Wk 24 of triple therapy Qualified for shortened therapy, %65 (24 wks)44 (28 wks) SVR, % Relapse, %99 Adverse events more frequent in PI arms Rash, anemia, pruritus, nausea Anemia, dysgeusia Jacobson IM, et al. AASLD Abstract Poordad F, et al. N Engl J Med 2011; 364:

Summary of telaprevir and boceprevir in treatment-experienced patients Telaprevir 1 Boceprevir 2  Significantly improved SVR rates in prior relapsers, partial responders, and null responders  Phase III trial included null responders  Telaprevir taken for 12 weeks  PR lead-in phase not required  Treatment duration is 48 weeks, or 24 weeks for eligible prior relapsers  Significantly improved SVR rates in prior relapsers and partial responders  Phase III trial excluded null responders  Boceprevir taken for:  32 weeks in non-cirrhotic relapsers and partial responders  44 weeks in those with compensated cirrhosis and in all null responders  PR lead-in phase is required  Treatment duration is 48 weeks 1. Telaprevir EU SmPC 2. Boceprevir SmPC

Resistencia a los inhibidores de la proteasa Las mutaciones de resistencia se desarrollan muy rápidamente (1-2 semanas en monoterapia). Es esencial que los pacientes reciban adecuadamente tratamiento con pegIFN/RBV junto con los IPs (estimular cumplimiento). No se debe reducir la dosis del IP. Interrumpir el IP si se produce un breaktrough virológico (aumento de HCV RNA)

Stopping Rules for Telaprevir and Boceprevir Telaprevir [package insert] Boceprevir [package insert] Time PointTVR + PegIFN/RBV BOC + PegIFN/RBV Wk 4 Discontinue all therapy if HCV RNA > 1000 IU/mL N/A Wk 12 Discontinue all therapy if HCV RNA > 100 IU/mL Wk 24Discontinue all therapy if detectable HCV RNA Any Discontinue protease inhibitor if pegIFN/RBV discontinued for any reason

IFN-Free Combination Therapies with 2 or More DAAs DRUG COMBOS CLASSCOMPANYPHASE BMS (Asuprenavir)+ BMS (Daclatasvir) PI+NS5a BMS2a Danoprevir + Mericitabine+/- RBV PI+NIRoche/ Genetech 2b Tegobuvir+ GS NNI+PI Gilead2a BI BI /- RBV PI+NNIBoehringer Ingelheim 2a

IFN RBV DAA RBV? DAA IFN RBV ¿Podremos curar la hepatitis C sin IFN?