COINFECCION VIH-VHC: Actualizaciones diagnósticas y terapeúticas

Transcripción

1 COINFECCION VIH-VHC: Actualizaciones diagnósticas y terapeúticas Dr. Víctor Asensi Unidad de E.Infecciosas-VIH Hospital Universitario Central de Asturias Universidad de Oviedo Oviedo 30/4/ 2013

2 Coinfección VHC/VIH: epidemiología en España Aproximadamente un 30% de los pacientes con VIH estan coinfectados VIH Hep C ~ pacientes ~ pacientes ~ pacientes

3 Prevalencia seriada de coinfección por VHC en VIH+ España CoRIS-MD and CoRIS HCV IDU Clinical Infectious Diseases 2009; 48:

4 Datos Epidemiológicos Mortalidad No Oportunista en VIH+ Cohorte HOPS (EEUU) Proporción de muertes por enfermedades NO oportunistas Muerte por enfermedades No oportunistas Porcentaje del total entre 2000 y , , , , , , P<.0001 para la tendencia 0 Hepatic Pulmonary Cardiovascular Renal Palella FJ et al. 11th CROI. 2004; Abstract 872.

5 Datos Epidemiológicos Ingresos por Enfermedad Hepática Estudio Transversal Retrospectivo. H U de Valme (Sevilla). Entre 1998 y 2005: 1138 VIH+ hospitalizados, 72 (6,3%) por enfermedad hepática. P*=0.254 P*=0.014 P*<0.001 % de los ingresos * En relación al periodo OR (IC 95%) N Adaptado de: del Valle J. Enf Infecc Microbiol Clin. 2008;26:500

6 FIBROSIS HEPÁTICA CÓMO MEDIRLA Y PARA QUÉ

7 Fibrosis hepática: Cómo medirla? Técnicas no invasivas: Tests sanguíneos: Simples y disponibles rutinariamente (APRI,FORNS,FIB-4) No disponibles rutinariamente (FIBROTEST) Técnicas de imagen: Elastografía transitoria hepática (ETH, Fibroscán) Otros

8 Tests sanguíneos sencillos Índice de Forns, APRI y FIB-4 Puntos de corte VPP % VPN % Predicción de F 2 Forns (Plaquetas, GGT, edad y colesterol) APRI (Plaquetas y AST) Predicción de F 3 FIB-4 (Plaquetas, edad, AST y ALT) Macías et al. Gut 2006;55: Sterling RK et al. Hepatology 2006;43:

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10 Elastometría transitoria hepática: Puntos de corte de rigidez hepática optimizados en la coinfección por VIH/VHC. F 1. Valor de corte 6 kpa VPP (%) 58 VPN (%) 90 Error de clasificación, n (%) 5 (15) F 2. Valor de corte 9 kpa VPP (%) 87 VPN (%) 74 Error de clasificación, n (%) 5 (12.5) F=4. Valor de corte 14.6 kpa VPP (%) 86 VPN (%) 94 Error de clasificación, n (%) 13 (10) Vergara et al. Clin Infect Dis 2007; 45: Macías J et al. J Hepatol 2008; 49:

11 Algoritmo diagnóstico de fibrosis Paciente coinfectado por VIH/VHC Elastometría transitoria 6 KPa KPa (Indeterminado) KPa 14.6 KPa Asumir F0-F1 APRI + Índice de Forns Asumir F2-F3 Asumir F=4 APRI <1.5 e Índice de Forns <6.9 APRI 1.5 ó Índice de Forns 6.9 FIB-4 <3.25 Biopsia hepática u Monitorizar otros progresión marcadores no invasivos Resultado indeterminado Asumir F2 Vergara et al. Clin Infect Dis 2007; 45: Macías J et al. J Hepatol 2008; 49:

12 Predicción de complicaciones de la cirrosis Probabilidad de descompensación según la RH basal en pacientes cirróticos Cohorte prospectiva de cirróticos coinfectados por VIH/VHC (HEPAVIR, ) 3% 7% 19% RH < 40 KPa N = 239. Cirrosis: RH 14 KPa Predictores de descompensación: CPT. Coinfección por VHB. Viremia VHC. RH. Probabilidad de descompensaciónn p= % 26% 37% RH 40 KPa Meses Merchante et al. Hepatology Aceptado

13 Predicción de varices esofágicas con necesidad de tratamiento profiláctico 21 KPa, VPN=100% Pineda JA, et al. J Acquir Immune Defic Sydr 2009; 51:

14 100 Fibrosis hepática: Para qué medirla? Evolución de la respuesta al tratamiento de los genotipos 1 del VHC en monoinfección % % Tasa de RVS (%) % IFN % IFN + RBV % Peg-IFN + RBV 2 4 DAA + Peg- IFN + RBV 5 8 DAAs McHutchison JG, et al. N Engl J Med 1998;339: ; 2. Fried M, et al. N Engl J Med 2002;347: Manns MP, et al. Lancet 2001;358:958 65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140: Jacobson IM, et al. Hepatology 2010;52(Suppl):427A; 6. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A 7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Foster GR, et al. Hepatol Int 2011;5(Suppl.1):14

15 Fibrosis basal y respuesta a telaprevir naïve Tx VHC (ADVANCE) Jacobson IM, et. al. N Engl J Med 2011; 364:

16 Fibrosis basal y respuesta a telaprevir en tratados VHC (REALIZE) Prior Relapsers Prior Partial Responders Prior Null Responders Pooled T12/PR48 Pbo/PR48 SVR (%) n/n = 144/16712/38 53/62 2/15 48/57 2/15 34/47 3/17 10/18 0/5 11/32 1/5 24/59 1/18 15/38 0/9 7/50 1/10 Stage No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis Zeuzem S, et al. Presented at: EASL: The International Liver Congress 2011; March 30 - April 3, 2011; Berlin, Germany. Oral Presentation 5.

17 Rigidez hepática como herramienta de priorización de terapia Diferir tto Monitorizar progresión RH Tratar Máxima prioridad Tto urgente Rigidez hepática 6 kpa F0-F1 9 kpa F2-F kpa F4 21 kpa Exclusión varices con riesgo de sangrado 40 kpa Riesgo de descompensación de cirrosis

18 Visión General del Manejo de la Coinfección VIH/VHC 1 Tratamiento antirretroviral 2 Tratamiento de la hepatitis C 3 Trasplante de hígado

19 Beneficios del TARV en coinfectados 1 2 Efectos sobre la fibrosis El control del VIH enlentece la progresión de la fibrosis hepática 1 Efectos sobre la Hª natural de la hepatopatía El TARGA reduce la mortalidad de causa hepática en coinfectados 2 También reduce la mortalidad hepática en coinfectados con cirrosis descompensada 3 1. Macías J et al. Hepatology 2009,50: Qurishi N, et al. Lancet. 2003:362: Merchante et al. AIDS 2006, 20:49 57

20 Inconvenientes del TAR: Hepatotoxicidad Vispo E, et al. JAC 2010; 65:

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22 El objetivo primario del tratamiento de la hepatitis C es la erradicación del VHC = Respuesta Viral Sostenida (RVS)

23 Beneficios de la RVS 1 Erradica la infección por VHC (recidivas <1%) Swain MG, et al. Gastroenterology. 2010;139:159 2 Interrumpe y revierte el proceso de fibrosis hepática Camma C et al. Hepatology 2004; 39: Reduce descompensaciones y muerte hepática Veldt BJ, et al. Ann Intern Med. 2007;147(10):677 Berenguer J, et al. Hepatology. 2009;50:407 4 Reduce la incidencia de Hepatocarcinoma Watanabe S, et al. Hepatol Res 2011; 41: 955 Berenguer J, et al. 6th IAS Conference Abstract # TUPE175 5 En VIH/VHC+ reduce progresión VIH y mortalidad no-hepática Berenguer J, et al. 17th CROI, Abstract # 167

24 Definitions of failure on prior Peg-IFN/RBV therapy HCV RNA level Null response Breakthrough Partial response Non-response Relapse 2 log 10 drop Detection limit Treatment Weeks Adapted from Shiffman M. Curr Gastroenterol Rep 2006 Neumann A, et al. Science 1998; De Bruijne J, et al. Neth J Med 2008

25 Recomendaciones GESIDA/PNS/AEEH Tratamiento Hepatitis C en Coinfectados (Sep 2009) Peg-IFN + RBV x 48 sem todos los genotipos Peg-IFN 2a = 180 μg/semana Peg-IFN 2b = 1-1,5μg/Kg/semana RBV = mg/dia según peso

26 Proposed optimal duration of HCV therapy in HCV/HIV co-infected patients (EACS 2011) W4 W12 W24 W48 W72 HCV-RNA negative HCV-RNA positive G2/3 G1/4 >2 log drop in HCV-RNA 24 weeks therapy* HCV-RNA negative HCV-RNA positive G2/3 G1/4 Stop 48 weeks therapy 72 weeks therapy <2 log drop in HCV-RNA Stop *In patients with baseline low viral load and minimal liver fibrosis. W, week; neg, negative; pos, positive; G, genotype.

27 EACS 2011

28 Eficacia del PEG-IFN+RBV en Coinfectados RVS (%) APRICOT LAGUNO PRESCO HEPAVIR Torriani FJ. N Engl J Med 2004; 351: Laguno M. Hepatology 20; 292: Nuñez M. AIDS Res Hum Retroviruses 2007; 23: Pineda JA. J Antimicrob Chemother 2007; 60:

29 El genotipo CC en el SNP rs C/T de la IL-28B ejerce un efecto beneficioso sobre la probabilidad de alcanzar RVS a pegifnα+rbv, principalmente en pacientes coinfectados VIH/VHC con genotipo VHC 1/4 Tasa de RVS en los diferentes genotipos del VHC de acuerdo al SNP rs Predictores de RVS a la terapia pegifnα/rbv en pacientes coinfectados VIH/VHC CT/TT patients CC patients Rallón et al. AIDS 2010; 24:F23-9

30 Probabilidades de RVS a Peg-IFN + RBV Según Genotipo, IL28B y ARN-VHC N=433 pacientes VIH/VHC, tratados con Peg-IFN + RBV (Análisis OT) 100% 90% 80% IL28B genotype no CC 80% CC 81% 77% 86% 70% 60% 68% 67% 61% % SVR 50% 40% 30% 41% 37% 30% 20% 17% 17% 10% HCV-RNA load 0% N= HCV Genotype GT 1 GT 4 GT 2/3 Neukam K et al. CROI Abstract 945.

31 Inconvenientes del tratamiento actual de la hepatitis C 1Baja aplicabilidad 2Eficacia insuficiente 3Problemas de tolerabilidad y toxicidad 4Duración excesiva

32 Nuevos tratamientos para la hepatitis C

33 HCV GT-1 SVR Rates Over Time According to the Type of anti-hcv Therapies HCV HCV/HIV IFN IFN + RBV Peg-IFN + RBV Peg-IFN+ RBV + Boceprevir/Telaprevir 15-20% 35-40% 45-50% 70-75% % 61-74%

34 otential targets for anti-hcv therapy Entry-Inhibitors Ribavirin TLR-Agonists Therapeutic Vaccine Other IFNs PEG-IFN lambda NS3 Protease- Inhibitors Cyclophilin Inhibitors NS5A Replication Complex Inhibitors (RCI) NS5B-Polymerase Analogue Inhibitors (NI, NNI)

35 Comparison of direct antiviral agents Class Potency Barrier to resistance Toxicity and drug interactions HCV genotype coverage NS3 Protease inhibitors (boceprevir, telaprevir, simeprevir, asunaprevir, faldaprevir, ABT-450) High Low Variable Multiple DDI 1 Other genotypes NS5B Polymerase analogue inhibitors Nucleos(t)ide (sofosbuvir) Moderate High High Mitochondrial toxicity PK interactions with other N(t)s All Non nucleoside (ABT-333, ABT-072) NS5A replication complex inhibitors (RCI)(ledipasvir, daclatasvir, ABT-267) Low Moderate Moderate High Very low Variable 1 Low Variable Variable Cyclophilin Inhibitors Moderate High Low All

36 Anti-HCV drugs in development Cyclophilin NS5B Nucleosides Mericitabine IDX-184 Alisporivir Phase II ABT-450 NS3 Protease ACH-1625 NS5A BMS GSK Ledipasvir ABT-267 Sofosbuvir Daclatasvir Phase III Boceprevir Launched Telaprevir Faldaprevir Asunaprevir Vaniprevir Simeprevir Danoprevir GS-9256 GS-9451 VX-222 Setrobuvir MK-5172 NS5B Non-Nucleosides Tegobuvir BMS BI ABT-333 ABT-072

37 New antivirals for HCV Host target: interferon lambda, alisporivir Virus target: NS3 protease inhibitors: Boceprevir, telaprevir TMC-435, BI-1335, danoprevir, asunaprevir, ABT-450, MK-5172, GS-9451 NS5B polymerase inhibitors: Nucles(t)ides: Sofosbuvir, Mericitabine, PSI-7977 Non-nucleosides: tegobuvir, setrobuvir, BI-7127,VX-222, ABT-333, ABT-072 NS5A replication complex inhibitors : Daclatasvir, ABT-267, GS-5885

38 Treatment Targets against HCV Receptor binding and endocytosis Transport and release Fusion and uncoating (+) RNA Virion assembly Translation and polyprotein processing RNA replication Boceprevir NS3/4A Protease Inhibitors Telaprevir Faldaprevir/Simeprevir/ABT-450

39 NS3/4A Protease Inhibitors Boceprevir Telaprevir

40 110 Team Study Design (HIV-HCV co) Part A: no ART T/PR TVR + PR PR Follow-up SVR PR48 (control) Pbo + PR PR Follow-up SVR Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC) T/PR TVR + PR PR Follow-up SVR PR48 (control) Pbo + PR PR Follow-up SVR Weeks (EFV)=efavirenz; (TDF)=tenofovir; (FTC)=emtricitabine; (ATV/r)=ritonavir-boosted atazanavir; (3TC)=lamivudine; (T) TVR=telaprevir 750 mg q8h or 1125 mg q8h (with EFV); Pbo=Placebo; (P) Peg-IFN=pegylated interferon alfa-2a (40 kd) 180 µg/wk; (R) RBV=ribavirin 800 mg/day or weight-based (1000 mg/day if weight <75 kg, 1200 mg/day for if weight 75 kg; France, Germany) Roche COBAS TaqMan HCV test v2.0, LLOQ of 25 IU/mL (pts with values below 25IU/mL were reported as <25 detectable or undetectable)

41 110 Team Study Design Undetectable HCV RNA at Week 12 (ITT) Percent of patients with HCV RNA Undetectable n/n = No ART EFV/TDF/FTC ATV/r+TDF+FTC/3TC Total 68 PR Total 5/7 12/16 8/14 25/37 1/6 1/8 1/8 3/22 14 Telaprevir + PR PR

42 HIV antiretroviral Studies completed Atazanavir/r Fosamprenavir/r Lopinavir/r Efavirenz Raltegravir Tenofovir Studies not completed Darunavir, etravirine and rilpivirine Abacavir/zidovudine ENSAYO CLÍNICOS DE INTERACCIONES ENTRE TELAPREVIR Y ARVs Recommendation Clinical and laboratory monitoring for hyperbilirubinemia is recommended Not recommended TVR dose increase necessary (1125 mg q8h) No dose adjustment required Increased clinical and laboratory monitoring is warranted Studies on going/planned UDP-glucuronosyltransferase: uridine 5'-diphospho-glucuronosyltransferase An effect of telaprevir on UDP-glucuronyltransferases cannot be ruled out and may affect the plasma concentrations of abacavir or zidovudine (not studied)

43 Study Design Weeks Arm 1 PEG2b +RBV 4 wk Placebo + PEG2b + RBV 44 wk Follow-up SVR-24 wk Arm 2 PEG2b +RBV 4 wk Boceprevir + PEG2b + RBV 44 wk Follow-up SVR-24 wk Futility Rules Two-arm study, double-blinded for BOC, open-label for PEG2b/RBV 2:1 randomization (experimental: control) Boceprevir dose 800 mg, TID 4-week lead-in with PEG2b/RBV for all patients PEG-2b 1.5 µg/kg QW; RBV mg/day divided BID Control arm subjects with HCV-RNA LLQ at TW 24 were offered openlabel PEG2b/RBV+BOC via a cross-over arm

44 Virologic Response Over Time (% HCV RNA Undetectable) % Patients With Undetectable HCV RNA 3/34 3/64 5/34 24/64 8/32 35/62 11/32 43/61

45 Inhibidores proteasa NS3/4A Telaprevir Boceprevir Mecanismo acción Toxicidad Metabolismo Transporte celular Inhibición reversible NS3 por unión covalente Ser 139 genotipo 1. Rash Alteraciones GI Anemia Síndrome perianal CYP3A4/5 y no CYP Inhibe CYP3A4/5 P-gp OATP1B1 Inhibe P-gp Anemia Neutropenia Alfa-ceto reductasa > CYP3A4/5 Inhibe CYP3A4/5 P-gp Inhibe OATP1B1

46 Interacciones TLV, BOC otros fármacos Telepravir Boceprevir Comedicación Comedicación Ibuprofeno Metadona 29% Midazolam % 5-fold 430% Escitalopram 35% Rifampicina 92% ( ) -- Ketoconazol 62% 46% 2.3-fold Atorvastatina -- 8-fold -- in vitro Anticonceptivos (etinilestradiol/ noretindrona) 28% / 11% -- 24% / 99%

47 Antirretrovirales que a dia de hoy se pueden utilizar con Boceprevir (BOC) o Telaprevir (TVR) BOC 3TC FTC ABC TDF EFV ATVr DRVr LPVr FPVr SQVr RAL MVC TVR

48 Esquema de tratamiento con AADs en pacientes con coinfección VHC/VIH TVR + PegIFN/RBV Peg-IFN /RBV >1000 UI/mL: Interrumpir 3 fármacos >1000 UI/mL: Interrumpir 3 fármacos Detectable: Interrumpir PR Detectable: Interrumpir PR Peg-IFN + RBV BOC+ Peg-IFN + RBV 100 UI/mL: Interrumpir todos fármacos Detectable: Interrumpir todos fármacos

49 Aspectos prácticos de los tratamiento con los nuevos Antivirales de Acción Directa: telaprevir y boceprevir telaprevir Coste Promedio comprimidos al día (2 cada 8 horas) - Duración del tratamiento en triple terapia: 12 semanas (504 comprimidos) - Inicio del tratamiento desde el primer día - No requiere refrigeración - No contiene lactosa como excipiente boceprevir Coste Promedio capsulas al día (4 cada 8 horas) - Duración del tratamiento en triple terapia: 44 semanas (3696 cápsulas) - Inicio del tratamiento sólo tras 4 semanas de tratamiento con peginterferon y ribavirina - Requiere refrigeración (2-8ºC) - Contiene lactosa como excipiente (672mg/día)

50 Management of HIV-HCV coinfected genotype-1 patients according to fibrosis stage and prior treatment outcome naive relapser nonresponder F0F1 Individual decision Individual decision / triple therapy defer F2F3 Triple therapy Triple therapy defer* F4 Triple therapy Triple therapy Triple therapy *monitor fibrosis stage annually, preferably with two established methods. Treat with triple therapy, if rapid progression. Ingilz & Rockstroh personal communication

51 Efficacy of Telaprevir and Boceprevir in HCV/HIV Coinfected Patients ANRS Trials 36 Cotte ANRS HC26 TelapreVIH Study (N=69) HIV+ patients treated with ART, who had previously failed 12 weeks pegifn- RBV for HCV genotype 1 co-infection. Null-responders with cirrhosis were excluded. EVR 16 = 88% (95% CI 81-96%) 37 Poizot-Martin ANRS-HC27 BocepreVIH Study (N=52) HIV+ patients treated with ART, who had previously failed 12 weeks pegifn- RBV for HCV genotype 1 co-infection. Null-responders with cirrhosis were excluded. EVR 16 = 63% (95% CI 51-75%)

52 Nuevos tratamientos para la hepatitis C diferentes de boceprevir y telaprevir

53 daclatasvir + asunaprevir + PEG-IFN+RBV

54 Efficacy of Simeprevir/Peg-INF/RBV in HCV/HIV Coinfected Patients 154LB Dieterich TMC435-C212 Study (N=106) - Simeprevir (TMC435) is a potent, oral, once-daily (QD), investigational hepatitis C virus (HCV) NS3/4A protease inhibitor with efficacy against HCV genotype 1 mono-infection - Patients who were treatment-naïve and non-cirrhotic (n = 50) or prior relapsers (n = 14) received a response-guided treatment (RGT) regimen of simeprevir (150 mg once daily) for 12 weeks plus PR for 24 or 48 weeks. Prior partial (n = 10) or null (n = 28) responders and patients with cirrhosis (3 treatment-naïve patients and 1 relapser) received treatment for 48 weeks. SVR 12 = 77% RVR - Naïve = 71% Simeprevir + PR - Relapsers = 93% - Partial responders = 80%

55 Efficacy of Faldeprevir/Peg-INF/RBV in HCV/HIV Coinfected Patients 40LB Dieterich STARTVerso 4 (N=308) - Faldaprevir (FDV; BI ) is an hepatitis C virus (HCV) NS3/4A protease inhibitor (PI) in late-stage clinical development for the treatment of HCV genotype 1 (GT1) infection. - HCV/HIV patients who were HCV treatment-naïve or relapsed after previous HCV therapy were randomized to receive FDV 120 or 240 mg once daily (QD) for 12 or 24 weeks, in combination with pegifn (180 µg once weekly) and weight-based RBV for 24 or 48 weeks (response guided). Week 12 <LLoQ TND - Treatment naïve = 82% - Relapsers = 91% Faldaprevir + PR

56 ELECTRON Sofosbuvir (SOF, GS-7977) Potent HCV-specific nucleotide analog (chain terminator) Safe and well tolerated Once daily, no food effect No significant drug interactions No safety signals in preclinical/clinical studies High barrier to resistance No virologic breakthrough to date Pan-genotypic antiviral effect Safe and well tolerated in ~1500 patients in Phase 2 and Phase 3 studies Gane EJ, et al. CROI 2013; Atlanta, GA. Oral #41LB 56

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58 IFN-free Regimens for Treating in HCV/HIV Coinfected Patients 155LB Lawitz COSMOS Study: Once-daily Regimen of Simeprevir + Sofosbuvir with or without Ribavirin. Hepatitis C Virus GT 1 Null Responders SVR 8 - SMV + SOF + RBV = 26/27 (96%) - SMV + SOF = 13/14 (93%)

59 ELECTRON Ledipasvir (GS-5885) HCV NS5A inhibitor NS5A essential for RNA replication and post-replication assembly and secretion 1 Picomolar potency against genotype 1a and 1b HCV 2 Effective against signature NS5B-resistant mutant S282T 3 1. Guedj J, et al. Proc Natl Acad Sci U S A 2013 [epub]; 2. Lawitz E, et al. EASL 2011, poster 1219; 3. Cheng G, et al. EASL 2012, poster 1172; Gane EJ, et al. CROI 2013; Atlanta, GA. Oral #41LB 59

60 ELECTRON STUDY Previously treated GT1 HCV-monoinfected patients Results: Efficacy Patients with HCV RNA <LOD* over Time, n/n (%) SOF + RBV SOF + LDV + RBV Treatment-naïve (n = 25) Null responder (n = 10) Treatment-naïve (n = 25) Null responder (n = 9) Week 1 8/25 (32) 1/10 (10) 11/25 (44) 0/9 (0) Week 2 17/25 (68) 7/10 (70) 22/25 (88) 4/9 (44) Week 4 25/25 (100) 10/10 (100) 25/25 (100) 8/9 (89) EOT 25/25 (100) 10/10 (100) 25/25 (100) 9/9 (100) SVR4 22/25 (88) 1/10 (10) 25/25 (100) 9/9 (100) SVR12 21/25 (84) 1/10 (10) 25/25 (100) 9/9 (100) *Analyzed by TaqMan HCV Test 2.0 with limit of detection (LOD) of 15 IU/mL. Includes 1 patient who stopped all treatment due to an SAE at week 8; this patient subsequently achieved SVR24. EOT, end of treatment; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir. 60

61 SPARE, COSMOS,ELECTRON Sofosbuvir (SOF) Studies SPARE 1 COSMOS 2 ELECTRON 3 Patient Population GT-1 difficult to treat patients (Part 1 N=10 in METAVIR F0-F2, Part 2 METAVIR F0-F4 N=50) GT-1 null responders to prior PEG/RBV with METAVIR F0-F2 (N=80) GT-1 naïve (N=25) and null responders(n=9) Regimen Part 1: SOF 400 mg QD + weight-based RBV (WBR) Part 2: SOF 400 mg QD + weightbased RBV or low dose RBV (LDR, 600 mg QD) SOF 400 mg QD + simeprevir (SMV) 150 mg QD ± RBV SOF 400 mg QD + ledipasvir (GS-5885) + RBV Treatment Duration 24 wks 12 or 24 wks 12 wks SVR SVR12 Part 1: 100% (mitt) Part 2: 71% WBR; 55% LDR (mitt) SVR8 SMV+SOF+RBV x12w: 96% SMV+SOF x12w: 93% SMV+SOF+RBV x24w: 67% SMV+SOF x24w: 100% SVR12 Treatment-naïve: 100% Null responder: 100% Safety Summary No SAEs or AE discontinuations No SAEs attributed to study drugs; 1 AE discontinuation No tx-related SAEs or AE discontinuations 1. Osinusi 61 A, et al. CROI 2013; Atlanta, GA. Oral #157 61

62 ABT ABT-450/r+RBV

63 IFN-free Regimens for Treating in HCV/HIV Coinfected Patients 38 Lawitz 12 Weeks of ABT-450/Ritonavir + ABT-072/333 + Ribavirin. ABT-450 = NS3 protease inhibitor, QD. ABT-333 and ABT-072 = Non-nucleoside NS5B polymerase inhibitors, QD. SVR 24 - Treatment naïve = 86-95% - Non-responders = 47%

64 IFN-free Regimens for Treating in HCV/HIV Coinfected Patients 39 King ABT-450/r + ABT ABT Ribavirin Optimal Treatment Duration (8, 12 or 24 weeks) ABT-450 = NS3/4A protease inhibitor, QD ABT-267 = NS5A replication complex inhibitor, QD ABT-333 = Non-nucleoside NS5B polymerase inhibitor, BD. SVR 24 [12 weeks] - Treatment naïve (N=237) = 89-99% - Null-responders (N=90) = 89-93%

65 Liver Disease Severity among HIV+ Patients in Madrid, Spain (N=1549) 2002 (N=1560) Liver cirrhosis 178 (12%) 104 (7%) <.001 P González-García J et al. Submitted to 19 th CROI 2012

66 Liver Disease Severity among HIV+ Patients in Madrid, Spain (N=1549) 2002 (N=1560) Liver cirrhosis 178 (12%) 104 (7%) <.001 Indication of OLT 20/178 (11%) 16/104 (15%).327 On waiting list for OLT 9/20 (45%) - OLT performed 3/20 (15%) - P González-García J et al. Submitted to 19 th CROI 2012

67 Miro, 726 Spain USA Italy Germany UK Argentina Portugal Switzerland Total Liver Retransplantation (relt) In HIV- Infected Patients: A Multinational Cohort ( ) Number Primary LT Number relt (%) 14 (5) 9 (7) 5 (4) 4 (13) 2 (8) 1 (11) 1 (8) 1 (10) 37 (6)

68 Rubens. Prometeo encadenado.museo Filadelfia