έλαβαν σύγχρονα αντι-ιικά φάρμακα

Επαναθεραπεία σε ασθενείς με χρόνια ηπατίτιδα C που έλαβαν σύγχρονα αντι-ιικά φάρμακα Αναπληρωτής Καθηγητής Γαστρεντερολογίας, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών, Ιατρική Σχολή, Παν/κή Γαστρ/κή Κλινική, Γ.Ν.Α. «ΛΑΪΚΟ»

SVR12 (%) Η πιθανότητα αποτυχίας είναι μικρή αλλά υπαρκτή 4 6 12 96 94 88 SVR12 No SVR12 n/n = (77/21) GT1 Clinical Trials (38/99) GT1 Real World (6/74) GT3 Clinical Trials

Γιατί μπορεί να αποτύχει η θεραπεία με DAAs? Κακή συμμόρφωση Αλληλεπιδράσεις με άλλα φάρμακα Μη ενδεδειγμένο θεραπευτικό σχήμα Ανεπαρκής διάρκεια θεραπείας

Παράγοντες που πρέπει να εκτιμηθούν επί αποτυχίας της θεραπείας Προηγούμενο σχήμα DAA classes RBV Διάρκεια θεραπείας Χαρακτηριστικά του ασθενή Κίρρωση BMI Νεφρική νόσος Αντοχή Άλλες παράμετροι Συμμόρφωση DDIs

Κλινικοί προβληματισμοί Χρειάζεται επιπλέον διερεύνηση? Ποιος είναι ο ρόλος του ελέγχου αντοχής στην επαναθεραπεία? Μπορεί ο ασθενής να πάρει RBV? Μήπως πρέπει να περιμένω μέχρι να έχω περισσότερες θεραπευτικές επιλογές? Υπάρχει περίπτωση να έχουμε επιδείνωση της ηπατικής λειτουργίας? Ποιες είναι οι διαθέσιμες θεραπευτικές επιλογές?

Resistance Characteristics of HCV Antiviral Classes Class Antiviral Potency NS3 protease inhibitor [1] +++ to ++++ GT Activity Resistance Barrier FDA Approvals 1, 4 (± 2, 3, 6) Low to high Simeprevir (13) Paritaprevir (14) Grazoprevir (16) Voxilaprevir (17) Glecaprevir (17) NS5B nucleotide [2] ++++ 1-6 Very high Sofosbuvir (13) NS5B nonnucleoside [2] ++ 1 Low Dasabuvir (14) NS5A inhibitor [3] ++++ 1, 4, 6 (± 2, 3) Low to high Ledipasvir (14) Daclatasvir (15) Ombitasvir (14) Elbasvir (16) Velpatasvir (16) Pibrentasvir (17) 1. Clark VC, et al. Liver Int. 13;33(suppl 1):-84. 2. Gerber L, et al. Liver Int. 13;33(suppl 1):85-92. 3. Pawlotsky JM. J Hepatol. 13;59:375-382.

Resistance Testing Approaches Ultradeep or next-generation vs population sequencing What is broadly commercially available: HCV GT1 NS3 and GT1 and GT3 NS5A drug resistance assays GT1 assays are subtype specific (1a vs 1b)

Pts With NS5A RASs at VF (%) NS5A Resistance Selection Rate Upon Virologic Failure PI based: EBR/GZR: 94% OBV/PTV/RTV + DSV: 68% NS5A RAS Detection Among Pts With VF in LDV/SOF Phase II/III Trials 94.7 Nucleotide based: 66.7 LDV/SOF: 75% SOF/VEL: 93% SOF/VEL/VOX ( 6 wks): % SOF + EBR/GZR ( 8 wks): 37% n/n = 37.5 3/ 8 14/ 21 18/ 19 6 8 12 Treatment Duration (Wks) 3/ 3 24

Pts With Any NS5A RASs at > 1% (%) Detectable RASs (%) Durability of Treatment-Emergent NS5A RASs LDV + NNI + PI 98 98 95 86 EBR/GZR ± RBV Treatment-emergent NS5A RASs (n = 35) n/n = 62/ 63 VF Parent Study 58/ 58 42/ 43 45/ 45 Baseline FU-12 FU-24 FU-48 FU-96 Registry Study 52/ 55 5/ 58 Treatment-emergent NS3 RASs (n = 35) 12 24 36 48 72 84 96 18 1 132 Wks Post VF Dvory-Sobol H, et al. EASL 15. Abstract O59. Lahser F, et al. AASLD 16. Abstract 61.

Broad Cross-Resistance With Early-Generation NS5A Inhibitors Fold Change Genotype 1a Genotype 1b M28T Q3R L31M/V Y93H/N L31V Y93H/N Ledipasvir x > x > x/ > x > x/ > 1,x x > x/-- Ombitasvir > x > x < 3x > 1,x/ > x > 1,x < 1x x/5x Daclatasvir > x > x > x/ > x > x/ > 1,x < 1x x/5x Elbasvir x > x > 1x > x/ > x > x < 1x > x/-- Velpatasvir < 1x < 3x x/5x > x/ > x < 3x < 3x/-- Pibrentasvir < 3x < 3x < 3x < 1x/< 1x < 3x < 3x/< 3x

SVR12 (%) SVR12 (%) NS5A RASs Associated With Retreatment Failure With a Cross- Resistant Regimen 8-12 wk LDV/SOF-based treatment failures retreated with LDV/SOF for 24 wks (N=41) 71 33 n/n = 29/41 All 11/11 18/3 No Yes BL NS5A RASs n/n = 5/5 4/5 2/6 Q3R or M28T L31M Y93H/N BL RASs Lawitz E, et al. EASL 15. Abstract O5.

SVR12 (%) Roles of RBV and Longer Tx Duration in Overcoming Resistance, Optimizing Retreatment HCV-infected pts without SVR in previous phase II trials of SOF/VEL (n = 41) or SOF/VEL /VOX (n = 28) SOF/VEL / mg + RBV (N = 69) Wk 24 96 77 Cirrhosis: 26%; Previous relapse: 99% % GT2 Only 18% of GT1 with NS5A RASs Previous treatment: 41% VEL 25 mg, 74% < 12 wks n/n = 27/ 28 6/6 5/5 8/8 3/3 1/ 13 NS5A RASs: No Yes No Yes No Yes GT1 GT2 GT3 Gane EJ, et al. EASL 16. Abstract PS24.

SVR12, % (95% CI) Retreatment of Previous Short Duration SOF + EBR/GZR Failure Pts retreated with SOF + EBR/GZR + RBV for 12 wks 25 pts who experienced failure of short course SOF + EBR/GZR (4-8 wks) 22 GT1a, 3 GT1b experienced failure with 4 wks % with NS5A RASs 52% NS3 RASs 44% NS3/NS5A RASs n/n = 23/ 23 All 18/ 18 5/ 5 No Yes 4 Wks 6 or 8 Wks Cirrhosis 15/ 15 8/ 8 Previous Treatment Duration 5/ 5 No 18/ 18 Yes Baseline NS5A RASs Lawitz E, et al. AASLD 15. Abstract LB-12

SVR12 (%) QUARTZ-I: 3D + SOF ± RBV for DAA-Experienced Pts With GT1 HCV Wk 12 Wk 24 Noncirrhotic GT1a 3D + SOF + RBV (n = 14) 95 93 Cirrhotic GT1a 3D + SOF + RBV (n = 6) GT1b ±cirrhosis 3D + SOF (n = 2) 14/ GT1a had previous OBV/PTV/RTV + DSV failure; no previous LDV/SOF failure All GT1a No Cirrhosis GT1a Cirrhosis GT1b ±cirrhosis Poordad F, et al. EASL 16. Abstract 156.

POLARIS Phase 3 Program POLARIS-1 DAA-Experienced POLARIS-4 N = 415 N = 333 NS5Aexperienceexperienced Non-NS5A- ± cirrhosis ± cirrhosis GT 1 2 3 4 5 6 GT 1 2 3 4 5 6 SOF/VEL/VOX 12 weeks (n=263) Placebo (n=152) SOF/VEL/VOX 12 weeks (n=182) SOF/VEL 12 weeks (n=151)

POLARIS 1 SOF/VEL/VOX for 12 Wks after DAA Failure in GT1-6 HCV Randomized, double-blind, placebo-controlled phase III trial Wk 12 DAA-experienced pts with GT1-6 HCV and NS5A inhibitor experience (N = 415) SOF/VEL/VOX PO QD (n = 263) Placebo PO QD (n = 152) Bourlière M, et al. N Engl J Med. 17;376:2134-2146.

Patients, % 5 51 POLARIS 1 Prior NS5A Treatment (%) 3 27 11 13 1 133 263 7 263 3 263 33 263 LDV DCV OMB Other* Bourlière M, et al. N Engl J Med. 17;376:2134-2146.

SVR12, % POLARIS 1 SVR12 Results Overall and by Cirrhosis Status 96 99 93 6 relapses 1 on-treatment failure 2 withdrew consent 1 LTFU 1 withdrew consent 1 LTFU 6 relapses 1 on-treatment failure 1 withdrew consent 253/263 1/142 113/121 Overall No Cirrhosis Cirrhosis Bourlière M, et al. N Engl J Med. 17;376:2134-2146.

SVR12, % POLARIS 1 SVR12 Results by Genotype 97 96 95 91 1 relapse 1 on-treatment failure 1 withdrew consent 1 LTFU 4 relapses 1 relapse 1 withdrew consent 146 15 GT 1 97 11 45 45 5 5 74 78 GT 1a GT 1b GT 2 GT 3 GT 4 GT 5 GT 6 22 1 1 6 6 Bourlière M, et al. N Engl J Med. 17;376:2134-2146.

SVR12 (%) POLARIS 1 SVR12 by Baseline Resistance Associated Substitutions (RAS) 83% Baseline RASs (8/251) 98% SVR12 5.6% 96% SVR12 NS5A Only 17.1% No RASs Any RAS NS5A= 94% SVR NS3= % SVR NS3+NS5A= 97% SVR 28.7% 3.6% NS3+NS5A 42/43 NS3 Only 199/8 Bourlière M, et al. N Engl J Med. 17;376:2134-2146.

POLARIS 4 SOF/VEL/VOX for 12 Wks after DAA Failure in GT1-6 HCV Randomized, open-label, active-controlled phase III trial Wk 12 DAA-experienced pts with GT1-6 HCV and no NS5A inhibitor experience with or without cirrhosis (N = 333) SOF/VEL/VOX PO QD (n = 182) SOF/VEL PO QD (n = 151) Bourlière M, et al. N Engl J Med. 17;376:2134-2146.

Patients, % 7 69 POLARIS 4 Prior DAA HCV Treatment 5 3 1 14 11 4 231 12 37 47 SOF Other SOF+SMV Other Other NS5B NS5B + NS3 Other 2 5 Bourlière M, et al. N Engl J Med. 17;376:2134-2146.

POLARIS 4 SOF/VEL/VOX for 12 Wks after DAA Failure in GT1-6 HCV SVR 12 overall and by cirrhosis status SOF/VEL/VOX 12 weeks SOF/VEL 12 weeks % 97.8 9.1 98 94 98 86 1 relapse 1 death 2 lost to follow-up 1 breakthrough 14 relapses n/n= 178/182 136/151 Overall 96/98 77/82 81/84 59/69 No cirrhosis Cirrhosis Bourlière M, et al. N Engl J Med. 17;376:2134-2146.

POLARIS 4 SOF/VEL/VOX for 12 Wks after DAA Failure in GT1-6 HCV SVR 12 by genotype, % SOF/VEL/VOX 12 weeks SOF/VEL 12 weeks % 98 89 96 95 97 96 85 n/n= 53/54 39/44 Genotype 1a 23/24 21/22 31/31 32/33 Genotype 1b Genotype 2 52/54 44/52 19/19 Genotype 3 Genotype 4 Bourlière M, et al. N Engl J Med. 17;376:2134-2146.

SVR12 (%) POLARIS 4 SVR12 by Baseline Resistance Associated Substitutions (RAS) SOF/VEL/VOX 12 weeks 48% Baseline RASs (83/172) 94% SVR12 51.7% No RASs 22.6% NS5A Only 23.3% NS3 Only % SVR12 Any RAS NS5A=% SVR NS3= % SVR NS3+NS5A=% SVR 84/89 2.3% NS3+ NS5A 83/83 No treatment-emergent RASs were observed in the patient who relapsed following SOF/VEL/VOX Bourlière M, et al. N Engl J Med. 17;376:2134-2146.

SVR12 (%) POLARIS 4 SVR12 by Baseline Resistance Associated Substitutions (RAS) SOF/VEL 12 weeks 48% Baseline RASs (7/145)* 89% SVR12 9% SVR12 51.7% No RASs 23.4% NS5A Only 22.1% Any RAS NS5A=94% SVR NS3=91% SVR NS3+NS5A=5% SVR NS3 Only 67/75 2.8% NS3+ NS5A 63/7 In the SOF/VEL group, 1/15 patients with virologic failure developed Y93H or Y93C Bourlière M, et al. N Engl J Med. 17;376:2134-2146.

SVR12, % Integrated Efficacy Analysis of POLARIS 1 & 4 SOF/VEL/VOX for 12 Weeks in DAA-Experienced Patients 97 97 97 99 96 95 431 445 222 228 15 155 68 69 Total GT 1 Total GT 1a GT 1b GT 2 GT 3 GT 4 GT 5 GT 6 Other Breakthrough 1 1 1 Relapse 7 2 2 4 1 36 36 Other 6 3 2 1 2 1 126 132 39 41 1 1 6 6 1 1 Roberts, EASL 17, SAT-2

Integrated Efficacy Analysis of POLARIS 1 & 4 Prevalence and Impact on Treatment Outcome of VOX- and VEL-Specific RASs in DAA-Experienced Patients 98% SVR12 1.4% VOX 6/417 98% SVR12 55% No RASs 229/417 42% VEL 177/417 225/229 1.2% VOX + VEL 5/417 184/188 Sarrazin, EASL 17, THU-248

Integrated Efficacy Analysis of POLARIS 1 & 4 Baseline and Posttreatment Sequence Analysis in DAA-Experienced Patients With Relapse Study HCV GT NS3 RASs NS5A RASs NS5B NI RASs Baseline Relapse Baseline Relapse Baseline Relapse 1a QK QK Y93N Y93N None None 3a None None Y93Y/H Y93H E237G Assay failure POLARIS-1 3a None None Y93Y/H Y93H None None 3a None None A3K A3K None None 3a None None None None None None 4d None None L3R L3R Y93H None None POLARIS-4 1a None None None None None None Sarrazin, EASL 17, THU-248

MAGELLAN-1 Study, Part 2 Glecaprevir/Pibrentasvir in genotype 1 or 4 with failure to DAAs Randomisation Open-label W12 W16 18 years HCV genotype 1, 4, 5 or 6 HCV RNA 1 IU/mL Failure to DAA regimen (maximum of % NS5A naïve) Without cirrhosis or compensated cirrhosis (maximum 5%) No HBV or HIV co-infection N = 44 N = 47 GLE/PIB GLE/PIB SVR 12 SVR 12 GLE/PIB: / mg 3 tablets QD Poordad F et al. Hepatology 18;67:1253-.

MAGELLAN-1 Study, Part 2 Glecaprevir/Pibrentasvir in genotype 1 or 4 with failure to DAAs 12 weeks N = 44 16 weeks N = 47 Median age, years 57 56 Female, % 3 3 Race: white, % 77 75 Genotype 1a / 1b / 1e / 1 other / 4, % / 18 / / 2 / 71 / 22 / 2 / 6 / 2 Median HCV RNA, log 1 IU/mL 6.1 6.3 Compensated cirrhosis, % 34 26 Previous DAA regimen, % NS3/4A only (NS5A-naïve) NS5A only NS3/4A + NS5A Prior DAA treatment response, % On-treatment failure Virologic relapse Baseline NS3 RASs only, % Baseline NS5A RASs only, % Baseline NS3 + NS5A RASs, % Baseline characteristics 32 36 32 32 68 5 55 11 28 38 34 28 72 9 52 9 Poordad F et al. Hepatology 18;67:1253-.

MAGELLAN-1 Study, Part 2 Glecaprevir/Pibrentasvir in genotype 1 or 4 with failure to DAAs SVR 12 according to prior DAA class use GLE/PIB 12 weeks GLE/PIB 16 weeks % 89 88 79 % 91 94 81 44 14 16 14 All patients PI only NS5A only PI + NS5A 47 13 18 16 All patients PI only NS5A only PI + NS5A Breakthrough 1 Relapse 4 4 Poordad F et al. Hepatology 18;67:1253-.

MAGELLAN-1 Study, Part 2 Glecaprevir/Pibrentasvir in genotype 1 or 4 with failure to DAAs SVR 12 by NS3 and NS5A RASs GLE/PIB 12 weeks GLE/PIB 16 weeks % 83 % 96 25 No RASs 13 2 15 NS3 only NS5A only 5 NS3 + NS5A 13 4 23 No RASs NS3 only NS5A only 4 NS3 + NS5A Breakthrough 1 1 3 Relapse 3 1 Poordad F et al. Hepatology 18;67:1253-.

MAGELLAN-1 Study, Part 2 Glecaprevir/Pibrentasvir in genotype 1 or 4 with failure to DAAs 9 virologic failures : 4 relapses (R) and 5 virologic breakthroughs (B) Prior DAA regimen(s) Genotype Type of failure GLE/PIB 12 weeks NS3 RAVs NS5A RVAs Baseline Failure Baseline Failure LDV/SOF 1a B None A156V Q3E/K Q3K, Y93H SMV + SOF, LDV/SOF 1a R V36M, R155K V36M, R155K, A156T M28V, Q3R M28G, Q3R DCV 1a R None None Q3R, H58D Q3R, H58D ASV + DCV + BCV 1a R None None Q3G P29R, Q3G ASV + DCV 1b R None None L28M, P32 dél L28M, P32 dél 3PI, 2 NS5A 1a B GLE/PIB 16 weeks Y56H, D168E V36M, Y56H, D168E K24Q, Y93H K24R, K24Q, Q3H, Y93H LDV/SOF 1a B None A156V Q3R, L31M Q3R, L31M, H58D DCV, PTV/OBV + DSV 1a PTV/OBV + DSV 1a B B Y56H, D168A Y56H, D168A Y56H, A156G, D168A R155T, A156G, D168A M28T/V, Q3R, L31M Q3H, Y93H NA M28A, Q3H, H58D, Y93H Pilot-Matias T, EASL 17, Abs. SAT-4

MAGELLAN-3: GLE/PIB + SOF + RBV for 12-16 Wks for Retreatment After Failure of GLE/PIB Ongoing, open-label phase IIIb study Primary endpoint: SVR12 Noncirrhotic patients with GT1, 2, 4, 5, 6 HCV infection ± HIV coinfection with VF on/after GLE/PIB and no previous NS5AI or PI (N = 2) Cirrhotic and noncirrhotic patients with GT1-6 HCV infection ± HIV coinfection with VF on/after GLE/PIB ± previous NS5AI or PI (N = 21) GLE/PIB QD + SOF QD + RBV BID (N = 2) GLE/PIB QD + SOF QD + RBV BID (N = 21) Wk 12 Wk 16 Wyles D, et al. EASL 18. Abstract PS-.

SVR12 (%) MAGELLAN-3: Efficacy of GLE/PIB + SOF + RBV in Patients Who Experienced GLE/PIB Failure 95 96 86 Baseline RAS: NS5A RAS detected in 18/23 (78%) pts NS3 + NS5A RAS detected in 5/23 (22%) pts, all in 16-wk arm n/n 2/2 /21 22/23 6/7 2/2 14/14 GLE/PIB + SOF + RBV 12 Wks 16 Wks Total GLE/PIB + SOF + RBV 12 or 16 Wks GT1 GT2 GT3 VF occurred in 1 patient in 16-wk arm Wyles D, et al. EASL 18. Abstract PS-.

EASL 18 HCV Treatment Guidelines Recommendations for patients who experienced DAA regimen (PI and/or NS5AI) failure Failure of DAA (PI and/or NS5AI)-Containing Regimen Retreatment Recommendation ± Compensated cirrhosis SOF/VEL/VOX for 12 wks ± Compensated cirrhosis with predictors of lower response* GLE/PIB + SOF for 12 wks Very difficult to cure: NS5A RASs after 2 failures of PI and/or NS5AI-containing regimens Decompensated cirrhosis SOF/VEL/VOX or GLE/PIB + SOF: + RBV for 12 wks, no RBV for 16-24 wks, or + RBV for 16-24 wks SOF/VEL + RBV for 24 wks *Advanced liver disease, multiple courses of DAA-based treatment, complex NS5A RAS profile. EASL HCV Guidelines. J Hepatol 18.

AASLD/IDSA Recommendations for DAA-Experienced Pts HCV GT Duration, Wks 1 12 Previous Experience NS3/4A NS5B NS5A GLE/PIB SOF/LDV (no cirrhosis) SOF/VEL 2* 12 NA GLE/PIB SOF/VEL (1b) SOF/VEL/VOX (1a) GLE/PIB SOF/VEL SOF/VEL/VOX 3 12 SOF/VEL/VOX SOF/VEL/VOX SOF/VEL/VOX ± RBV 4, 5, 6 12 SOF/VEL/VOX SOF/VEL/VOX SOF/VEL/VOX NA *Recommendations for any SOF + RBV experienced pt. RBV if NS5A inhibitor failure and cirrhosis. AASLD/IDSA. HCV guidance. September 17.

Συμπεράσματα Οι διαθέσιμες σήμερα θεραπευτικές επιλογές εξασφαλίζουν την εκρίζωση του ιού της ηπατίτιδας C στην πλειονότητα των ασθενών. Αναπόφευκτα, ένα μικρό ποσοστό ασθενών δεν ανταποκρίνεται στη θεραπεία. Η νέα γενιά αντι-ιικών επιτυγχάνει τη θεραπεία των ασθενών εκείνων που δεν ανταποκρίνονται στα αρχικά σχήματα. Ο έλεγχος μεταλλαγών που επιφέρουν αντοχή του ιού δεν είναι απαραίτητος στους περισσότερους ασθενείς που απέτυχαν στο αρχικό σχήμα με DAAs. Σύνθετοι συνδυασμοί, παράταση διάρκειας θεραπείας και/ή προσθήκη ριμπαβιρίνης επιστρατεύονται για τους ελάχιστους ασθενείς με προχωρημένη νόσο, επανειλημμένες αποτυχίες και συνδυασμό μεταλλαγών του ιού.