Tratamiento en los fracasos a antivirales de segunda generación Jose Luis Calleja Profesor Titular de Medicina Hospital Universitario Puerta de Hierro Madrid 2012 Agenda • Fracaso de los diferentes regímenes – Impacto y persistencias de las resistencias • Evidencia cientifica de eficacia en retratamiento • Recomendaciones de las Guias • Conclusiones EVIDENCIAS FRACASOS SOF+SMV Estudio Fase 2: COSMOS Lawitz AASLD 2013 EVIDENCIAS FRACASOS SOF+SMV Estudio Fase 2: COSMOS Lawitz EASL 2014 EVIDENCIAS FRACASOS SOF+SMV Estudio vida real: TARGET 44/357 (12,3%) Jensen AASLD 2014 Cohort of patients with treatment start on or before 4/15/14 ; BLOQ=Below Level of Quantitation; SOF Containing Regimens G3 G3 G3 G3 SOF + DCV: ALLY-3 •PEG + RBV •PEG + RBV + SOF •SOF + RBV •SOF + DCV GT 3; n=150 Study Week ⸗ SOF 400 mg + DCV 60mg QD 24w 0 12 24 36 9/13 32/34 11/19 73/75 DCV, daclatasvir; SOF, sofusbuvir; LLOQ, TD or TND, lower limit of assay quantitation, target detected or target not detected. Nelson DR, et al. AASLD 2014. Oral LB-3 ATU Genotype 3 ■ Most GT 3-infected patients were: ̶ ̶ ̶ ̶ male (75%) HCV mono-infected (83%) cirrhotic (77%) and treatment experienced (73%) ■ Median baseline platelet count: 118.5 x 109/L (range: 31–387) ■ Median baseline albumin: 39.0 g/L (range: 13–56) Hezode C, et al. EASL 2015; Poster LP05 7 SVR4 Rates With DCV + SOF ± RBV By Treatment Duration 12 Weeks 24 weeks 22/29 52/59 Cirrhotic patients 11/12 5/6 Non-cirrhotic patients ■ Treatment discontinuations were related to adverse events (1 patient), death (2 patients), or patient decision (1 patient) Hezode C, et al. EASL 2015; Poster LP05. 8 ALLY-1: Multicenter, Open-Label Phase 3 Study Advanced cirrhosis N = 60 DCV 60 mg QD + SOF 400 mg QD + RBV Follow-up Post-liver transplant N = 53 DCV 60 mg QD + SOF 400 mg QD + RBV Week 0 Week 12 Week 24 SVR12a Week 36 ■ Primary endpoint: SVR12 in GT1 in each cohort ■ 12 weeks of treatment: DCV 60 mg + SOF 400 mg + RBV – RBV initially 600 mg/day, adjusted to 1000 mg/day based on Hgb levels and CrCl ■ Advanced cirrhosis patients with treatment interrupted by liver transplantation could receive an additional 12 weeks of treatment immediately post-transplant a HCV RNA < lower limit of assay quantitation (LLOQ) at posttreatment Week 12 by Roche HCV COBAS TaqMan Test v2.0 (LLOQ 25 IU/mL). 9 Baseline Disease Characteristics by Child-Pugh Class Advanced cirrhosis cohort Parameter Ascites present, n (%) Encephalopathy present, n (%) Native MELD score, n (%)a < 10 10–15 16–20 21–25 > 25 Albumin, median (range) g/dL INR, median (range) T bilirubin, median (range) mg/dL Platelets, median (range) × 109 cells/L α-fetoprotein, median (range) ng/mLb a Entry criteria: MELD scores 8–40. b Included 6 HCC patients: 1 CP A, 2 CP B, 3 CP C Class A N = 12 Class B N = 32 Class C N = 16 0 2 (17) 21 (66) 19 (59) 16 (100) 16 (100) 7 (58) 5 (42) 0 0 0 3.7 (3.0–4.3) 1.2 (1.1–1.4) 0.9 (0.4–1.7) 7 (22) 20 (63) 5 (16) 0 0 0 3 (19) 9 (56) 3 (19) 1 (6) 3.2 (2.6–4.4) 1.4 (1.0–1.9) 1.6 (0.6–4.4) 2.5 ( 2.0–3.4) 1.7 (1.2–3.9) 3.0 (1.1–6.4) 94 (41–179) 86 (35–182) 72 (35–147) 13.0 (3.4–49.6) 13.3 (1.8–86.2) 7.7 (1.8–149) 10 SVR12 by CohortSVR12 by Cohort GT 1 (Primary Endpoint) SVR12, %a All Patients Advanced cirrhosis Post-transplant Advanced cirrhosis Post-transplant ■ In a regression analysis, no difference by gender, age, IL28B, or HCV RNA in the advanced cirrhosis cohort with GT 1 a HCV RNA < LLOQ (25 IU/mL); error bars reflect 95% confidence intervals. 11 SVR12 by Cohort Patients Without SVR12 SVR12, %a All Patients 9 relapses 1 HCV RNA detectable at end of treatment 3 relapses Advanced cirrhosis Post-transplant ■ Patients with relapse are being retreated with DCV + SOF + RBV for 24 weeks a HCV RNA < LLOQ (25 IU/mL); error bars reflect 95% confidence intervals. 12 Resistance Analyses Baseline resistance polymorphisms ■ NS5A-28, -30, -31, or -93 polymorphisms detected in 22 of 112 patients – 82% (18/22) achieved SVR12 ■ 10/14 in cirrhosis cohort; 8/8 in post-transplant cohort – 90% (81/90) without NS5A polymorphisms achieved SVR12 ■ 39/45 in cirrhosis cohort; 42/45 in post-transplant cohort ■ No NS5B-S282 variants detected at baseline or failure NS5A resistance-associated variants in patients with virologic failure Advanced cirrhosis Post-transplant 10 3 NS5A RAVs at baseline, n/Na 4/10 0/3 NS5A RAVs at failure, n/Na 10/10 3/3 Virologic failures, N a Assessed by population-based sequencing. 13 Long-Term Persistence of HCV NS5A Variants After Treatment With NS5A Inhibitor Ledipasvir David Wyles1, Alessandra Mangia2, Wendy Cheng3, Stephen Shafran4, Christian Schwabe5, Wen Ouyang6, Krishna Chodavarapu6, John McNally6, Brian Doehle6 , Evguenia Svarovskaia6, Michael D. Miller6, Hongmei Mo6, Hadas Dvory-Sobol6 1University of California San Diego, California, USA; 2Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy; 3Royal Perth Hospital, Western Australia, Australia; 4University of Alberta, Edmonton, Canada; 5Auckland Clinical Studies Ltd, Auckland, New Zealand; 6Gilead Sciences, Inc., Foster City, California, USA EASL 2015, Vienna Objectives ♦ To characterize NS5A RAVs in patients who failed HCV treatment with ledipasvir (LDV) in the absence SOF Quantify – Proportion of patients with any NS5A RAV over time Characterize – Change in number and type of NS5A RAVs detected in any given patient over time 15 Study Design Sequence Registry Study LDV + VDV + TGV + RBV (n=50) LDV ±VDV ±TGV + PEG + RBV (n=26) BL FU-12 FU-24 FU-36 FU-48 FU-96 Plasma samples for sequence analysis ♦ Patients who did not achieve SVR in Gilead studies evaluating direct-acting antiviral (DAA) regimens including LDV but not SOF were enrolled in a 3-year registry study ♦ Plasma samples for sequence analysis were collected at baseline and follow-up Weeks 12, 24, 36, 48, and 96 TGV, tegobuvir (GS-9190); VDV, vedroprevir (GS-9451). 16 Methods ♦ Sequencing analysis – Population sequencing performed on sample from the parent study – Deep sequencing using the MiSeq platform was used for all samples – 1% detection threshold was used for identification of variants ♦ NS5A RAVs at positions 24, 28, 30, 31, 32, 58, 93 that confer >2.5-fold reduced susceptibility to LDV in vitro were included in the analysis 17 Patients With NS5A RAVs (%) Proportion of Patients With Any NS5A RAVs at More Than 1% 62/63 Parent Study 58/58 42/43 45/45 52/55 50/58 Registry Study ♦ NS5A RAVs persisted in majority of patients for 96 weeks 18 Efficacy of the 3D Regimen In phase 3 trials, the recommended regimen* of 3D ± RBV achieved an SVR rate of 97% across a broad range of HCV GT1a and GT1b patients • GT1a Virologic Failure Rate % (n/N) GT1b No Cirrhosis 3D + RBV Cirrhosis 3D + RBV No Cirrhosis 3D Cirrhosis 3D + RBV 2.4 (14/593) 3.3 (4/121) 0 (0/301) 1.5 (1/68) – 19 (18 GT1a, 1 GT1b) of 1083 patients (1.8%) receiving 3D recommended regimens experienced virologic failure; breakthrough or relapse – Pooled resistance analysis included 2510 patients in Phase 2 and 3 trials that received the 3D regimen irrespective of dose or duration of treatment • 67 GT1a and 7 GT1b failures (2.9% of total population) *3D without RBV for GT1b noncirrhotic patients, 3D+ RBV for GT1a and all cirrhotic patients, 12 week treatment duration for all except GT1a cirrhotic patients who receive 24 weeks Krishnan P., et al. EASL 2015 Pooled Analysis: Resistance-Associated Variants that Emerged in the 3D ± RBV Regimens in Phase 2 and 3 Target Resistance-Associated Variants NS3 At any NS3 amino acid position: 36, 43, 55, 56, 132, 155, 156, 168 R155K D168 any (A/F/H/I/L/N/T/V/Y) D168V NS5A NS5B 3D (All Pooled) N = 2510 Number of Virologic Failures N (%) GT 1a GT 1b N = 67 N=7 52(78%) 4 (57%) 9 (13%) 43 (64%) 35 (52%) 4 (57%) 3 (43%) At any NS5A amino acid position: 28, 30, 58, 93 48 (72%) 2 (29%) M28A/T/V Q30E/K/R Y93H 20 (30%) 29 (43%) - 2 (29%) At any NS5B amino acid position: 316, 414, 446, 553, 554, 556, 558, 559, 561 39 (59%) 2 (29%) C316Y M414I/T S556G/R 2 (3%) 3 (5%) 23 (35%) 1 (14%) 1 (14%) 1 (14%) Krishnan P., et al. EASL 2015 Persistence of TEVs in NS3 in PTV/r-Containing Regimens (GT1a) Non-Cirrhotics n/N (%) 2D ± RBV Time window Cirrhotics n/N (%) 3D ± RBV 3D + RBV All PTV/rContaining Regimens n/N (%) PTW24 PTW48 PTW24 PTW48 PTW24 PTW48 PTW24 PTW48 TEVs (any) 6/19 (32) 1/17 (6) 19/37 (51) 3/32 (9) 8/11 (73) 1/8 (13) 31/67 (46) 5/57 (9) D168 (any) 4/16 (25) 0/16 (0) 11/30 (37) 1/30 (3) 6/9 (67) 1/7 (14) 21/55 (38) 2/53 (4) R155K 2/5 (40) 1/5 (20) 6/6 (100) 1/2 (50) 2/2 (100) LTFU 10/13 (77) 2/7 (29) 2D = PTV/r + (DSV or OBV); PTW = post-treatment Week; LTFU = lost to follow-up • • • • Treatment duration or regimen did not affect rate of decline of TEVs in NS3 TEVs in NS3 declined to a prevalence of 9% at PTW48 The most common TEV selected by PTV was D168V, which was less persistent than the R155K variant that was infrequently detected with PTV regimens (more common with simeprevir) Among patients experiencing virologic failure with the recommended regimen, 60% had TEVs at PTW24 and none had TEVs at PTW48 in NS3 Krishnan P., et al. EASL 2015 Persistence of TEVs in NS5A in OBVContaining Regimens (GT1a) Non-Cirrhotics n/N (%) 2D ± RBV Time window Cirrhotics n/N (%) 3D ± RBV 3D + RBV All OBV-Containing Regimens n/N (%) PTW24 PTW48 PTW24 PTW48 PTW24 PTW48 PTW24 PTW48 TEVs (any) 13/13 (100) 10/10 (100) 42/42 (100) 31/32 (97) 13/15 (87) 8/9 (89) 68/70 (97) 49/51 (96) M28V/T 6/6 (100) 5/5 (100) 20/21 (95) 14/14 (100) 6/6 (100) 2/2 (100) 32/33 (97) 21/21 (100) Q30E/K/ R 7/8 (88) 5/6 (83) 23/24 (96) 15/16 (94) 8/9 (89) 5/6 (83) 38/41 (93) 25/28 (89) 2D = PTV/r + OBV; PTW = post-treatment Week • Treatment duration or regimen did not affect rate of decline of TEVs in NS5A • Predominant TEVs at NS5A amino acid positions M28 and Q30 remained detectable at similar levels at PTW24 and 48 Krishnan P., et al. EASL 2015 Persistence of TEVs in NS5B in DSV-Containing Regimens (GT1a) Non-Cirrhotics n/N (%) 2D ± RBV Time window Cirrhotics n/N (%) 3D ± RBV 3D + RBV All DSV-Containing Regimens n/N (%) PTW24 PTW48 PTW24 PTW48 PTW24 PTW48 PTW24 PTW48 TEVs (any) 3/6 (50) 4/6 (67) 21/28 (75) 15/23 (65) 9/10 (90) 3/7 (43) 33/44 (75) 20/35 (57) S556G 2/2 (100) 1/2 (50) 20/22 (91) 14/17 (82) 5/6 (83) 2/3 (67) 27/30 (90) 17/22 (77) Other 1/4 (25) 1/4 (25) 1/12 (8) 1/9 (11) 5/5 (100) 0/4 (0) 7/21 (33) 3/18 (17) 2D = PTV/r + DSV; PTW = post-treatment Week; Other = M414T, A553D/T/V, G554S, G558R, D559G/N • Treatment duration or regimen did not affect rate of decline of TEVs in NS5B • Predominant TEV S556G remained detectable at PTW24 and 48 • Minor NS5B TEVs A553D/T/V, G554S, G558R, D559G/N declined through PTW24 and 48 Krishnan P., et al. EASL 2015 Importancia de las resistencias ♦ La mayor parte de los pacientes con fracaso virológico desarrollan resistencias ♦ Las resistencias en NS3 desaparecen en poco tiempo, pero las resistencias al NS5a y b persisten en el tiempo ♦ La aparicion del polimorfismo S262T que confiere resistencia a sofosbuvir es excepcional ♦ El impacto de las resistencias NS5a en la RVS es variable: – Basales o desarrolladas durante el tratamiento – Tipo de resistencias – Número de resistencias Agenda • Fracaso de los diferentes regímenes – Impacto y persistencias de las resistencias • Evidencia cientifica de eficacia en retratamiento • Recomendaciones de las Guias • Conclusiones Successful Retreatment With Sofosbuvir-containing Regimens for HCV Genotype 2 or 3 Infected Patients who Failed Prior Sofosbuvir Plus Ribavirin Therapy Rafael Esteban1, Lisa Nyberg2, Jay Lalezari3, Liyun Ni4, Brian Doehle4, Bittoo Kanwar4, Diana Brainard4, GM Subramanian4, William T. Symonds4, John G. McHutchison4, Maribel Rodriquez-Torres5, Stefan Zeuzem6 1Vall d’Hebron Hospital, Barcelona, Spain; 2Kaiser Permanente, San Diego, CA, USA; 3Quest Clinical Research, San Francisco, CA, USA; 4Gilead Sciences, Inc., Foster City, CA, USA; 5Fundacion de Investigacion, San Juan, Puerto Rico; 6JW Goethe University Hospital, Frankfurt, Germany International Liver Congress 2014, London, UK Results: On Treatment Viral Response and SVR 12 28/28 50/50 28/28 50/50 24/26 25/40 ♦ Relapse accounted for all virologic failures Error bars represent 95% confidence intervals. 27 Results: GT 3 SVR12 by Cirrhosis Status 13/14 7/8 17/23 7/15 28 EVIDENCIAS EN RESCATE ELECTRON-2 LONESTAR EVIDENCIAS EN RESCATE ELECTRON-2 Results, Prior Sofosbuvir-Treated GT 1 Patients Re-treatment SOF+RBV 12 wk Prior Null Responders SOF+RBV 12 wk Treatment Naïve n=4 SVR12 (%) n=6 n=1 GS-9669 + SOF +RBV 12 wk Treatment Naïve • n=8 LDV/SOF +RBV 6 wk Treatment Naïve All 19 previous SOF-regimen failures had relapsed Gane EASL 2014 19/19 19/19 EVIDENCIAS EN RESCATE 98% 98% SVR 100% SVR 88% No NS5A RAVs at baseline 12% NS5A RAVs n=44/50* n=6/50 n=43/44 *1 patient’s baseline results were not available. Wyles D et al. AASLD 2014 Abstract # • No patients had SOF-associated variant, S282T, detected at baseline – 2 patients had NS5B treatment-emergent variant# L159F at baseline and achieved SVR 31 EVIDENCIAS EN RESCATE LONESTAR Lawitz aasld 2013 Retreatment of Patients Who Failed 8 or 12 Weeks of Ledipasvir/Sofosbuvir-Based Regimens With Ledipasvir/Sofosbuvir for 24 Weeks Eric Lawitz1, Steven Flamm2, Jenny C. Yang3, Phillip S. Pang3, Yanni Zhu3, Evguenia Svarovskaia3, John G. McHutchison3, David Wyles4, Paul Pockros5 1Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, USA; 2Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; 3Gilead Sciences, Inc., Foster City, California, USA; 4University of California, San Diego, California, USA; 5Scripps Clinic, La Jolla, California, USA EASL 2015, Vienna Study Design GT 1 Retreatment Wk 0 Wk 12 Wk 24 Wk 36 SOF failures (n=51) LDV/SOF + RBV LDV/SOF failures (n=41) LDV/SOF SVR12 SOF failures (advanced LDV/SOF + RBV SVR12 liver disease) 1. Wyles D, et al. AASLD 2014. Abstract 235. 98% SVR121 SVR12 Demographics and Baseline Characteristics GT 1 Retreatment LDV/SOF 24 Weeks N=41 Mean age, y (range) 58 (35–71) Male, n (%) 34 (83) Black/African American, n (%) 10 (24) IL28B non-CC, n (%) 38 (93) GT 1a, n (%) 34 (83) Mean HCV RNA, log10 IU/mL (range) Cirrhosis, n (%) Presence of NS5A RAVs 6.2 (4.5–7.4) 19 (46) 15 (79) Prior HCV treatment, n (%) LDV/SOF ± RBV 33 (80) LDV/SOF + GS-9669 8 (20) Prior HCV treatment duration, n (%) 8 weeks Presence of NS5A RAVs 12 weeks Presence of NS5A RAVs 30 (73) 19 (63) 11 (27) 11 (100) Results: On-Treatment Viral Kinetics and SVR HCV RNA <LLOQ (%) GT 1 Retreatment 13/41 39/41 41/41 40/41 30/41 29/41 ♦ One patient experienced on-treatment breakthrough at Week 16 EOT, end of treatment. Error bars represent 95% confidence intervals. 36 SVR12 (%) SVR12 by Subgroup GT 1 Retreatment 15/22 14/19 No No Yes Yes Cirrhosis 24/30 5/11 11/11 No Prior Treatment Duration 18/30 Yes Baseline NS5A RAVs ♦ All 11 patients without NS5A RAVs received 8 weeks of prior treatment 37 SVR12 (%) SVR12 by Baseline NS5A RAVs GT 1 Retreatment 11/1 1 11/16 7/14 Number of NS5A RAV(s) *M28T (n=1). 5/5 4/5 2/6 Type of Single NS5A RAV 38 Conclusions GT 1 Retreatment ♦ 71% of patients who failed prior LDV/SOF-containing regimens achieved SVR12 when retreated with LDV/SOF for 24 weeks ♦ The presence of baseline NS5A RAV(s), which was more likely to develop with longer prior LDV/SOF treatment, was associated with virologic failure ♦ Emergence of S282T was observed in 3 of 12 virologic failure patients ♦ Retreatment with LDV/SOF is feasible in patients who have failed prior LDV/SOF-based regimens 39 Agenda • Fracaso de los diferentes regímenes – Impacto y persistencias de las resistencias • Evidencia cientifica de eficacia en retratamiento • Recomendaciones de las Guias • Conclusiones RESCATE ¿QUÉ DICEN LAS GUÍAS? Recommended Regimens for TreatmentExperienced GT1 HCV Pts Population Noncirrhotic Compensated Cirrhotic Regimen Duration, Wks LDV/SOF 12 Regimen Duration, Wks Prior PegIFN/RBV GT1a or 1b GT1a or 1b LDV/SOF 24 LDV/SOF + RBV 12 GT1a OMV/PTV/RTV + DSV + RBV 12 OMV/PTV/RTV + DSV + RBV 24 GT1b OMV/PTV/RTV + DSV 12 OMV/PTV/RTV + DSV + RBV 12 SMV + SOF ± RBV 12 SMV + SOF ± RBV 24 LDV/SOF ± RBV 24 LDV/SOF 24 LDV/SOF + RBV 12 GT1a or 1b Prior SOF GT1a or 1b Defer therapy* Prior PI GT1a or 1b GT1a or 1b LDV/SOF 12 *Based on limited available data, pts without advanced fibrosis and without an urgent need for HCV treatment should defer antiviral therapy pending additional data or consider clinical trial. EASL Guidelines 2015 Sofosbuvir + Riba – Genotipo 1 : • SOF/LED , Abbvie y SOF/DAC – Genotipo 2 y 3 : SOF/DAC r – Genotipo 4 : SOF/LED, Abbvie 2D y SOF/DAC Sofosbuvir + Simeprevir – SOF/LED y SOF/DAC EASL Guidelines 2015 • SOF + Inh NS5A – Sofosbuvir + Simeprevir – Genotipo 2 y 3 : SOF/DAC 24 semanas o 12 sem con RIBA • Abbvie 3D – SOF /DAC y SOF /LED 24 semanas con RIBA HCV Reinfection in Phase 3 Studies of Sofosbuvir Christoph Sarrazin,1 Vasily Isakov,2 Evguenia Svarovskaia,3 Ross Martin,3 Krishna Chodavarapu,3 Charlotte Hedskog,3 Diana Brainard,3 Michael Miller,3 Hongmei Mo,3 Jean-Michel Molina,4 Mark S. Sulkowski5 1J. W. Goethe-University Hospital, Frankfurt am Main, Germany; 2Institute of Nutrition, Moscow, Russia; 3Gilead Sciences, Inc., Foster City, California, USA; 4University of Paris Diderot, Paris, France; 5Johns Hopkins University School of Medicine, Baltimore, Maryland, USA EASL 2015, Vienna Concordance of SVR12 and SVR24 in SOF Clinical Studies Concordance 99% Patients achieved SVR12 N=3004 Patients achieved SVR24 n=2992 Did not achieve SVR24 n=12 Full-length NS5B successfully deep sequenced n=10 Only short NS5B fragment sequenced due to low HCV viral load n=2 45 Investigation of Relationship Between Baseline and Rebound Virus Genotype or subtype at baseline and at failure Same Different Phylogenetic analysis Related Distantly related Not related Phylogenetic analysis of quasispecies (baseline, FU-24) Mixed Late relapse Different Reinfection 46 Phylogenetic Analyses Genotype Patient Study Baseline Post-Treatment Phylogenetic Distance 1 PHOTON-2 4d 1a Not related* 2 PHOTON-1 1a 1a Not related* 3 PHOTON-2 1a 1a Not related* 4 GS-US-334-0119 1b 1b Not related* 5 FUSION 3a 3a Not related† 6 PHOTON-2 1a 1a Distantly related 7 FUSION 3a 3a Distantly related 8 PHOTON-1 3a 3a Closely related 9 VALENCE 3a 3a Closely related 10 VALENCE 3a 3a Closely related 11 FISSION 3a 3a Closely related 12 PHOTON-2 3a 3a Closely related† *Similar results were obtained for NS3, NS5A, and NS5B when sequences were available. †Short fragment NS5B sequencing only, due to low viral load. 47 CONCLUSIONES • Es imprescindible generar nueva evidencia en pacientes no respondedores a los diferentes regímenes orales • Parece razonable ser conservador en las pautas en pacientes con riesgo de recidiva • Mientras tanto: – No respuesta a SOF + IP : SOF+ Inh NS5a – No respuesta a SOF + Inh NS5a: • Genotipo 1 y 4 : SOF + IP • Otros genotipos : Alargar el tratamiento y añadir RIBA
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