Failure after treatment with DAAs: What to do? Marc Bourliere, MD White Nights of Hepatology Hôpital Saint Joseph Saint Petersburg Marseille France 2-3 th June 16
Disclosures Board member for : Schering-Plough, Merck, Janssen, Gilead, Boehringer Ingelheim, BMS, Novartis, Roche, AbbVie, GSK, Vertex, Idenix Speaker for : Roche, Schering-Plough, Merck, Janssen, Gilead, BMS, Abbvie
Failure is a rare event in the DAAs era: Large real-world data confirm clinical trial results: 16236 GT-1 patients ( EASL 16) SIM/SOF SOF/LDV 3D SOF/DCV % 90% 80% 70% 60% 50% 40% 30% % 10% 0% 93% 93% 95% 94% 94% 93% 87% 88% 89% 98% 97% 96% 95% 94% 86% 94% 95% VA VA / HIV TRIO N Italian Portugese Spanish German Nb =2363/4104/773 103/8/13 1378 343/ 73 /42 872 1504/1422 284/1836/390/528 No impact of HIV HBV, diabetes and obesity on SVR Follow the EASL Guideline (93% vs 87%) Hypo Alb <35g/l negative predictor of SVR McCombs J et al: LBP-510,McGinnis J et al: LBP-514, Afdhal N et al: LBP-519, Aghemo A et al: LBP-500, Marinho T et al: LBP-523, Crespo, J et al: LBP-511, Calleja JL et al: LBP-512, Mauss. S et al: SAT-263
Failure is a rare event in DAAs era even in cirrhotic: Large real-world data confirm clinical trial results: Cirrhotic patients SAEs : 8.1% and 4 pts died from cirrhosis complication SVR rates(itt) : GT-1: 91%, GT-2: 80%, GT-3: 73%, GT-4: 83% Deterding K et al. EASL 16: SAT-194
What to do in case of failure? Resistance testing?
Role of Resistance Testing The presence of resistance associated variants to DAAs prior to treatment may have an impact on SVR, especially in pts with previous DAA treatment experience and/or cirrhosis Consider resistance testing prior to retreatment in patients who fail to achieve HCV cure with DAAbased treatments EASL 15 : recommendation on treatment of Hepatitis C. J Hepatol 15
Resistance issue RBV NS5B NUC High barrier to resistance NS5A.I I. NNuc NS5B NS5B NNI NS3/4 PI Modest barrier to resistance (esp to GT1a) Low barrier to resistance (esp to GT1a) NS5B NUC NS3/4 IP PI NS5A.I Very few or no RAS RASs with short half-life RASs with long half-life
Patients with RAVs (%) Long term follow-up of NS5A RAVs after Ledipasvir failure 73 patients included in ledipasvir containing regimen who failed to treatment 99% have NS5A RAVs at failure Long term follow-up ( up to 2 years after treatment discontinuation by ultra deep sequencing % 98 % % 95 % 86 % 80 60 40 0 58/58 42/43 45/45 52/55 50/58 Baseline FU 12w FU 24w FU 48w FU 96w NS5A RAVs persist in the majority of patients 2 years after treatment discontinuation EASL 15 - D après Dvory-Sobol H et al., abstr. O059, actualisé
SVR12 (%) 24 Wks of LDV/SOF After Failure of 8-12 Wks of LDV/SOF-Based Therapy in GT1 Pts Results from single arm of prospective phase II trial GT1 HCV infected pts previously treated with LDV/SOF 90/400 mg QD LDV/SOF-based therapy (N = 41) NS5B variants with resistance to SOF emerged during retreatment in 33% of pts (4/12) with virologic failure S282T: n = 3 (out of 12) 80 60 40 71 68 74 80 46 24 Wks 60 n/n = 0 29/ 41 15/ 22 All No Yes Lawitz E, et al. EASL 15. Abstract O005. 14/ 19 Cirrhosis 24/ 30 5/ 11 8 Wks 12 Wks Previous Tx Duration 11/ 11 No 18/ 30 Yes BL NS5A RAVs
Re-treatment of Patients who Failed an IFN-Free Regimen The re-treatment regimen should contain Sofosbuvir because of the high barrier to resistance 1 or 2 other DAA(s), if possible with no cross-resistance with the DAA(s) already administered Ribavirin Treatment duration should be 12 or 24 weeks (recommended in F3-F4) EASL 15 : recommendation on treatment of Hepatitis C. J Hepatol 15
German resistance network : Prevalence of RAS in DAAs failure according to genotype Genotype 1 (n = 195) 2 % 3 % Genotype 3 (n = 69) 1 % 5 % 6 % 10 % No RAS NS5A 2 % 4 % 19 % 41 % 14 % NS3 + NS5A NS5A + NS5B NS3 NS5B NS3 + NS5B 32 % 61 % No RAS NS5B NS5A + NS5B NS5A + NS5B NS3 + NS5A NS3 + NS5A + NS5B RAS in 90 % of patients RAS in 39 % of patients Vermehren J, et al. EASL 16, Abs. PS103.
SVR (%) % of RAS German resistance network : SMV/SOF failure 40 n = 27/49 (55 %) 18 % 80 60 0 52 % No NS5A RAS alone 15 % No RAS NS3 NS5A NS5B NS5A + NS5B 4 % 4 % 7 % NS3 + NS5A NS3 + NS5B Retreatment with a regimen containing NS5A inhibitors LDV/SOF + RBV (n = 10) LDV/SOF + RBV (n = 13) PrOD + RBV (n = 3) PrOD + RBV (n = 1) 0 12 24 Weeks 80 60 40 0 Intermediate analysis: SVR 12 = 91 % (n = /22) 90 LDV/SOF + RBV PrOD + RBV 12 weeks. 24 weeks. 12 weeks. 24 weeks. Vermehren J. et al. EASL 16, Abs. PS103.
SVR (%) % of RASs German resistance network : LDV/SOF failure n = 11/90 (12 %) DCV/SOF failure n = 11/29 (38 %) 80 60 40 0 5 % No NS3 RAS alone 77 % No RAS NS3 NS5A NS3 + NS5B Q80K considered as minor variant 5 % 9 % 5 % NS5A + NS5B NS3 + NS5A + NS5B Retreatment with a regimen containing a PI SMV/SOF + RBV (n = 6) 80 Intermediate analysis: SVR 12 = 86 % (n = 6/7) 75 SMV/SOF + RBV (n = 11) 60 PrOD + RBV (n = 4) 40 PrOD + RBV (n = 1) 0 12 24 Weeks 0 SMV/SOF + RBV PrOD + RBV 12 weeks. 24 weeks. 12 weeks. 24 weeks. Vermehren J. et al. EASL 16, Abs. PS103.
% of RAS German resistance network : 80 NO SOF RAS PrOD Abbvie failure n = 5/27 (19 %) 60 40 0% % 40 % % % 0 No RAS NS5A NS3 + NS5B NS5A + NS5B NS3 + NS5A + NS5B Retreatment with a regimen containing a NS5B Nuc I. SOF + LDV + SMV + RBV (n = 1) SOF + LDV + RBV (n = 3) SOF + SMV + RBV (n = 1) 0 12 24 weeks Vermehren J. et al. EASL 16, Abs. PS103.
SVR (%) % of RAS German resistance network : 80 79 % No Y93H SOF/RBV failure n = 14/43 (42 %) 60 40 21 % 0 No RAS NS5A (A30K/S) Retreatment with a regimen containing a NS5A. I. Intermediate analysis: SVR 12 = % (n = 7/7) 90 DCV/SOF + RBV (n = 3) 80 60 DCV/SOF + RBV (n = 10) LDV/SOF + RBV (n = 1) 0 12 24 Weeks 40 0 DCV/SOF + RBV LDV/SOF + RBV 12 weeks. 24 weeks. 12 weeks. 24 weeks. Vermehren J. et al. EASL 16, Abs. PS103.
Retreatment of HCV DAAs failure according to EASL guidelines First line regimen SOF/TVR +/- RBV SOF/TVR +/- RBV SOF/TVR +/- RBV SOF/PEG RBV SOF/PEG RBV SOF/SMV +/-RBV SOF/SMV +/-RBV SOF/DCV +/-RBV SOF/DCV +/-RBV SOF/DCV 32 patients, 66% F4 Genotypes repartition G4 25 % G3 19 % G1 9% G2 13 % G1B 22 % G1A 12 % All the patients were exposed to the NS5B inhibitor during the first line (Sofosbuvir) or ombitasvir. All the seconde line have used sofosbuvir baseregimen Each First line of treatment 12 weeks 24 weeks Secondline of treatment represents a single patient HCV Genotype G1 G1A G1B G2 G3 G4 SOF/PEG RBV SOF/LDV +/-RBV SOF/DCV +/-RBV SOF/DCV +/-RBV SOF/LDV +/-RBV SOF/DCV +/-RBV SOF/LDV +/-RBV SOF/DCV +/-RBV SOF/LDV +/-RBV SOF/DCV +/-RBV 32 retreated patients 11 during 12 weeks 21 during 24 weeks % SVR 12 (21/21) Second line regimen 12 patients under treatment or follow-up Laurain A et al EASL 16 :FRI- 8
Retreatment of HCV DAA failures: upon where no to go!! Eleven patients (mean age: 56.2 years, range: 48-64) infected with: -HCV genotype 1 (1a: n=4 ; 1b: n=3) -HCV genotype 2 (n=1) -HCV genotype 4 (n=2) -HCV genotype 6 (n=1) All patients had compensated liver disease (fibroscan: 6.6-35.3 kpa) and failed to achieve SVR with previous all-oral regimen They had received SOF + DCV (n=6) ; DCV + SMV (n=1) ; SOF + SMV (n= 1) ; SOF + LDV (n=1) ; GRZ + EBV (n=1) ; Mericitabine + Danoprevir + ritonavir (n=1) ; without RBV for 12 weeks Geno type Baseline NS3 RAVs Baselin e NS5A RAVs M28A, Q30K Baseli ne NS5B RAVs Last ontreatment HCV RNA (UI/mL) SVR12 Failure NS3 RAVs Failure NS5A RAVs Failure NS5B RAVs 1a R155K, D168E None <12 (EOT) Relapse R155K, D168E M28A, Q30K None 1a R155K M28T None <12 (EOT) Relapse R155K Q30E None 1a R155K Q30K None <12 (Week R155K M28T, None 4) Q30K Relapse Discontin uation due to SAE* 1a None Q30K None <12 (EOT) Yes - - - 1b None L28I, R30S None <12 (Week 6) Unknown Discontin uation due to SAE* RA Substitution (RASs) should be assess before retreatment HCV resistance was assessed at retreatment baseline by means of population sequencing of the NS3 protease, 1b None Y93H (S556 <12 (EOT) Yes - - - NS5A and NS5B polymerase especially coding regions in those who have been treated previously G) Wk 12 Wk 24 Wk 36 SOF + DCV + SMV + RBV SVR12 with PI and NS5A I. 1b None None C316N <12 (EOT) Yes - - - 2 None None None <12 (EOT) Pending 4 D168E L28M, None <12 (EOT) Yes - - - L30C 4 None L30S, None <12 (Week Pending Y93H 12) 6 Y56H, D168C None None <12 (EOT) Yes - - - SAEs: Pulmonary arterial hypertension (n=1) ; Multi-organ failure possibly related to mitochondrial toxicity (n=1) - SOF+DCV+SMV+RBV for 24 weeks was associated with on-treatment response in all patients - However, One patient discontinued early due to SAE (possible mitochondrial toxicity) and virological outcome is pending - and at least 3 patients failed to achieve an SVR, one due to SAE (pulmonary arterial hypertension), the other two due to post-treatment relapse - Given the lack of other DAA class options, the latter patients should be considered incurable Hezode. C et al EASL poster THU-217
Just Around the Corner Sofosbuvir/velpatasvir
SOF/VEL + RBV 2 for 24 weeks : A good options for failure to NS5A inhibitors except in genotype 3 patients. SVR according to RAS and genotype G1 (n = 34) G2 (n = 13) G3 (n = 16) 82 % No RAS 28/34 18 % RAS 6/34 38 % No RAS 5/13 62 % RAS 8/13 19 % No RAS 3/16 81 % RAS 13/16 96 % SVR % SVR % SVR % SVR % SVR 77 % SVR 27/28 6/6 5/5 8/8 3/3 10/13 11/13 GT-3 patients G3 with Y93H mutations ; 9 (82 %) SVR 12 5 patients with 2 NS5A mutations; 5 SVR 12 3 patients with NS3 mutations; 3 SVR 12 Gane EJ. Et al. EASL 16, Abs. PS024
Market Authorization hypothesis SIM SOF/LDV SOF/VEL SOF/VEL/ GS-9857 ODV/AL33 5/SIM? SOF 14 15 16 17 18 DCV ABT-493 /ABT-530 SOF/DC V VIEKIRAX Exvira Gra/Elb 2DAA Gra/ MK-3682 /MK-8408 3DAA Pan genotypic activity
Treatment of patients who failed previous DAAs regimen SVR 12 SOF/ VEL/ GS-9857 12 weeks 1 relapse 127/128 63/63 21/21 34/35 9/9 All G1 G2 G3 G4, 6 Lawitz E. et al EASL 16, Abs. PS008 6 6 22 19 22 6 6 21 19 ABT-493 / ABT-530 12 weeks in GT-1 patients ITT mitt Poordad F. et al. EASL 16, Abs. GS11
SOF/VEL/GS-9857 for 12 weeks in genotypes 1 to 6 patients with DAAs failure Impact of baseline RAS on SVR 12 60 % Baseline RAS (77/128) % SVR 12 40 % No RAS (51/128) % NS5A RAS only 15 % NS3 RAS only 99 % SVR 12 51/51 23 % multiple RAS 76/77 2 % NS5B RAS only Lawitz E. et al. EASL 16, Abs. PS008.
HCV RNA (log 10 UI/mL) SOF/VEL/GS-9857 for 12 weeks in genotypes 1 to 6 patients with DAAs failure Relapse : prior treatment and RASs evolution 8 7 6 5 4 3 NS5A Y93H (> 99 %)* NS3 NS5B No RAS No RAS NS5A Y93H (> 99 %) NS3 Q80R (41 %) NS5B No RAS 2 1 0 SOF + RBV 32 weeks. Peg-IFN 8 sem. SOF/VEL + GS-9857 12 weels. Follow up S8 58 yo GT-3 women with cirrhosis, HCV RNA 7,0 log 10 IU/ml Lawitz E. et al, EASL 16, Abs. PS008.
SOF/VEL/GS-9857 for 12 weeks : A good option in GT-1 DAAs failure Monocenter phase 2 trial in GT1 patients with DAAs failure : G1a (88 %), cirrhosis (50 %) Two arms study : SOF/VEL/GS-9857 (second generation PI) 12 weeks vs SOF/VEL/GS-9857 + RBV 12 weeks. Previous treatment ( 6 weeks) SVR 12 96 6 % 31 % 14 % % NS5A 41 % (/49) No NS5A 59 % (29/49) 16 % 12 % NS5A NS3 NS5B 24/24 24/25 SOF/VEL/GS-9857 12 weeks. SOF/VEL/GS-9857 + RBV 12 weeks. Lawitz E. et al. EASL 16, Abs. PS021.
SOF/VEL/GS-9857 for 12 weeks : A good option in GT-1 DAAs failure HCV RNA (log10 UI/ml) Impact of RAS on SVR Resistance profil in the relapser NS5A % SVR 12 12/12 75 % baseline RAS (36/48) 25 % No RAS (12/48) 15 % NS5A RAS 29 % NS3 RAS 31 % Multiples RAS 97 % SVR 12 35/36 7 6 5 4 3 2 1 0 LDV/SOF 24 weeks. M28V (1,7 %) Q30H (3,2 %) L31M > 99 %) 0 RAS 0 RAS SOF/VEL/GS-9857 + RBV 12 weeks. M28T (> 99 %) Q30 L (2,4 %) Q30R (97,3 %) L31M (> 99 %) V36M (> 99 %) Q41R (> 99 %) D168G (96,4 %) D168S (2,4 %) 0 RAS FU-4 NS3 NS5B deep sequencing 61 yo African American male with cirrhosis and IL28B CC Lawitz E. et al. EASL 16, Abs. PS021.
ABT-493 and ABT-530 in GT-1 non cirrhotic DAAs failure patients 80 60 40 0 Dose ABT-493 ABT-530 Dose RBV 6 6 0 mg 1 mg 91 22 ITT 300 mg 1 mg 800 mg SVR 12 Impact of baseline RAS on SVR 12 300 mg 1 mg 0 mg 1 mg Modified ITT 300 mg 1 mg 800 mg 300 mg 1 mg Breakthrough 0 0 1 0 0 1 Relapse 0 1 0 0 1 0 Lost of FU 0 1 2 - - - 86 19 22 6 6 95 95 21 19 SVR 12 15/16 (94 %) SVR 12 6/6 ( %) NS3 and NS5A RAS (n = 16) NO RAS (n = 6) NS3 RAS only (n = 15) NS5A RAS Only (n = 10) SVR 12 = % among patient with baseline NS5A Y93 mutation SVR 12 9/10 (90 %) SVR = % among patients with baseline NS3 Q80 or R155 mutations SVR 12 15/15 ( %) Poordad F. et al. EASL 16, Abs. GS11.
Conclusions In case of DAAs failure consider resistance testing prior retreatment. The re-treatment regimen should contain Sofosbuvir because of the high barrier to resistance 1 or 2 other DAA(s), if possible with no cross-resistance with the DAA(s) already administered Ribavirin Treatment duration should be 12 or 24 weeks (recommended in F3-F4) For those with multiple RASs against NS3 and NS5A, and advance disease, retreatment must be cautious with available drug and future treatment may be more promising
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