Implications of HCV resistance and viral genotypes for the optimization of treatment Julia Dietz University of Frankfurt Department of Internal Medicine
Introduction • High sustained virologic response (SVR) rates (>90%) are achieved using IFN-free DAA (direct acting antivirals) combinations (DCV/SOF, LDV/SOF, VEL/SOF, EBR/GZR, PTVr/OBV/±DSV, ±RBV) • SVR rates are decreased by pre-existent RASs (resistance-associated substitutions), depending on several factors (pretreatment status, cirrhosis…) • For rescue therapies after DAA-failure RASs seem to be even more important* • Consideration of HCV geno-/subtype is recommended for DAA selection, as individual regimens exist and some GT are associated with a reduced treatment response * Lawitz et al., Retreatment of pts who failed 8 or 12 wks of LDV/SOF-based regimens with LDV/SOF for 24 wks. O005, EASL 2015.DCV, daclatasvir; LDV, ledipasvir; VEL, velpatasvir; EBR, elbasvir; GZR, grazoprevir; PTVr, paritaprevir/ritonavir; OBV, ombitasvir; DSV, dasabuvir; SOF, sofosbuvir; RBV, ribavirin
Frankfurt Resistance Database Characteristics Patient samples n=4240 HCV genotypes 1a, 1b, 1c-e 1700 (40%), 1554 (37%), 8 (<1%) HCV genotypes 2, 2k/1b, 3 105 (3%), 34 (<1%), 654 (15%) HCV genotypes 4, 5, 6 173 (4%), 10 (<1%), 2 (<1%) DAA-treatment-naive 2349 (55.4%) Insufficient data on treatment status / other** 914 (21.6%) Boceprevir/Telaprevir + PEG/RBV failure (BOC/TVR) 325 (7.6%) Sofosbuvir/RBV + PEG failure (SOF/P/R) 63 (1.5%) IFN-free DAA failures: 589 (13.9%) Sofosbuvir/RBV failure (SOF/R) 155 (3.7%) Simeprevir + Sofosbuvir ± RBV failure (SMV/SOF) 55 (1.3%) Daclatasvir + Sofosbuvir ± RBV failure (DCV/SOF) 89 (2.1%) Ledipasvir + Sofosbuvir ± RBV failure (LDV/SOF) 235 (5.5%) Paritaprevir/r + Ombitasvir ± Dasabuvir ± RBV failure (3D/2D) 55 (1.3%) • Resistance testing: population-based sequencing of NS3, NS5A and NS5B, analysis of DAA- specific RASs (>2-fold EC50) • NS3 RASs: F43I/L/S/V, Y56H, Q80K/R, S122R, R155G/K/T, A156G/T/V, D168A/E/G/H/I/N/T/V/Y • NS5A RASs : K24G/N/R, M28A/G/T/V, Q30E/H/L/R, L31I/F/M/V, P32L/F, S38F, H58D, A92K/T, Y93C/F/H/N • DSV NS5B RASs : C316H/N/Y, S368T, M414T, E446K/Q, Y448C, A553T/V, G554S*, S556G, G558R*, D559G/N*, Y561H • SOF NS5B RASs: L159F, S282T, C316N, L320F, V321A • Retrospective data collection of DAA failures (virologic treatment response, treatment initiation/duration)
Typical treatment-emergent RASs GT1a GT1b GT2 GT3 GT4 Regimen NS3 NS5A NS5B NS3 NS5A NS5B NS5A NS5B NS5A NS5B NS3 NS5A NS5B naive Q80K # # # # C316N L31M no # no # L30R no S556G RASs RASs RASs SMV/SOF R155K no L159F not applicaple not applicaple Q80R, no D168E RASs D168V C316N D168E RASs (NS3/NS5B) DCV/SOF Q30H/R no L31M L159F no patients Y93H S282T L28M S282T L31M RASs Y93H C316N (NS5A/NS5B) LDV/SOF Q30H/R S282T L31M L159F not applicaple no RASs no L28M S282T Y93H/N Y93H S282T RASs Y93C/ (NS5A/NS5B) C316N H/S 3D/2D R155K M28T/V S556G Y56H Y93H S556G not applicaple not applicaple D168V L28V (NS3/NS5A/NS5B) D168V Q30R D168V Y93H SOF/R no L159F no L159F not applicaple (NS5B) RASs C316N RASs green: 2-20-EC 50 fold-change compared to WT replicon # frequencies of natural RASs between 1-20% orange: 20-100 fold change red: >100 fold change • DAA-naive patients: low- to medium-level resistant RASs • DAA-experienced patients: high-level resistant RASs (> 80%), median sampling time >3 months after EOT, longer persistence of NS5A RASs Dietz et al. EASL 2016
Italian Study: Multiclass RASs in DAA failures NS5A inhibitor experienced patients: number of RASs n=310 DAA failure pts. n=198 NS5A failure pts. • Numbers of NS5A RASs were different according to the GT Overall 37% (73/198) of NS5A failing individuals had ≥ 2 RASs • Di Maio et al. EASL 2017
Theoretical (re)-treatment options according to RASs 98% 97% 100% (Re-)treatable patients without RASs 90% 84% 80% 80% 60% 40% 29% 20% 0% DAA-naive SOF/PR, SOF/RBV SMV/SOF DCV/SOF LDV/SOF 3D GT1 Dietz et al. EASL 2016
Theoretical (re)-treatment options according to RASs 100% 98% 97% 100% (Re-)treatable patients without RASs 90% 84% 80% 80% 60% 40% 29% 20% 0% DAA-naive SOF/PR, SOF/RBV SMV/SOF DCV/SOF LDV/SOF 3D DAA-naive GT1 GT2 Dietz et al. EASL 2016
Theoretical (re)-treatment options according to RASs 100% 100% 98% 97% 100% 95% 95% (Re-)treatable patients without RASs 90% 84% 80% 80% 60% 40% 29% 16% 20% 0% DAA-naive SOF/PR, SOF/RBV SMV/SOF DCV/SOF LDV/SOF 3D DAA-naive DAA-naive SOF/PR, SOF/RBV DCV/SOF LDV/SOF GT1 GT2 GT3 Dietz et al. EASL 2016
Theoretical (re)-treatment options according to RASs 100% 100% 100% 98% 97% 100% 95% 95% 95% (Re-)treatable patients without RASs 94% 90% 84% 80% 80% 60% 40% 29% 16% 20% 0% 0% DAA-naive SOF/PR, SOF/RBV SMV/SOF DCV/SOF LDV/SOF 3D DAA-naive DAA-naive SOF/PR, SOF/RBV DCV/SOF LDV/SOF DAA-naive DCV/SOF LDV/SOF 2D GT1 GT2 GT3 GT4 Dietz et al. EASL 2016
Real world data (UK): Prolonged retreatment • Virological failure 12 wks NS5A inhibitor/SOF => retreatment 24 wks, same regimen Retreatment GT1 p<0.05 100% Initial Treatment 80% • All retreated patients had RASs, but 50% Retreatment SVR 12 60% achieved SVR n=13 n=2 40% 46% 50% 20% 0% sof/LDV +/- sof + DCV +/- RBV RBV Retreatment GT3 100% Initial Treatment NS NS Retreatment • 70% of DCV (not LDV) treated patients 80% n=45 n=16 developed Y93H 60% SVR 12 • 60% achieved SVR 69% 63% 40% 20% 0% sof/LDV +/- sof + DCV +/- 12 weeks sof + • Treatment extension can overcome impact of RBV RBV DCV +/- RBV RASs overall n=128 DAA failure pts. Cheung et al. EASL 2017
Real world French study: RASs and retreatment • Initial treatment failure => retreatment using DAA class switch and/or intensified treatment (+RBV) Retreatment of Genotype 1 patients Virological response to retreatment (N=57) 100 100 100 92 90 88 80 85 At the time of retreatment 75% of patients had RASs in NS3 or NS5A 60 SVR (%) or NS5B (N=71 1 ) 40 20 17 35 6 22 9 12 17 40 6 26 10 13 0 Overall Genotype 1a Genotype 1b genotype 1 No RASs RASs overall n=159 DAA failure pts. • RASs at retreatment had effect on SVR rates in GT1a patients, not in other GT • RASs testing prior to retreatment may be useful for reinforced therapy 1 In total, 9/80 patients were excluded due to failed sequence analysis Chevaliez et al. EASL 2017
Real world data (FFM): Rescue according to RASs n=536 SMV/SOF± RBV LDV/SOF± RBV DCV/SOF± RBV PTV/OBV/±DSV±RBV SOF/RBV n=60 n=235 n=90 n=58 n=93 Cirrhosis, n (%) 38 (75)* 106 (50)* 39 (53)* 18 (36)* 42 (54)* +RBV, n (%) 9 (15) 63 (27) 17 (19) 29 (50) 93 (100) Prior Treatment 43 (77)* 109 (58)* 48 (75)* 27 (67)* 24 (55)* failure, n (%) Treatment Duration -/60/- 62/141/32 -/52/38 -/57/1 GT2: 12 wks. 8/12/24 wks., n GT3: 12-24 wks. * related to the number of patients with available data SMV/SOF DCV-/LDV-/SOF 3D SOF/RBV or DCV/SOF GT1 Failures GT1 Failures GT1 Failures GT3 Failures LDV/SOF or 3D SMV/SOF or 3D SOF + SMV/LDV DCV-/LDV-SOF ±RBV 12/24 wks ±RBV 12/24 wks ±RBV 12/24 wks ±RBV 12/24 wks SVR 30/33 (91%) SVR 7/7 (100%) SVR 18/20 (90%) SVR 28/30 (93% ) SVR 2/5 (40%) Vermehren et al. EASL 2016
GT3: Challenging genotype • Second most prevalent GT worldwide, rapid fibrosis progression and increased HCC risk • SVR rates were lower in patients with GT3 (particularly in presence of cirrhosis, prior treatment failure and RASs) SOF+RBV failures (n=73) 3% 8% no RASs Y93H A30K 89% Interim analysis: SVR 88% (n=21/24) Retreatment with an NS5A-Inhibitor (n=40) 100 90 100 89 75 80 VEL/SOF ± RBV (n=15) SVR (%) 60 VEL/SOF + RBV (n=1) 40 1 pt. with DCV/SOF ± RBV (n=9) VEL failure 20 did not take DCV/SOF ± RBV (n=14) 0 RBV DCV/SOF LDV/SOF VEL/SOF +RBV ±RBV ±RBV LDV/SOF + RBV (n=1) Week 0 12 24 FU12 Vermehren et al. EASL 2017
GT3: Optimization of retreatment Retreatment of GT3 patients who failed a first course of DCV+SOF therapy Prior PEG/R Gender Cirrhosis Y93H Retreatment Outcome experience DCV+SOF, 24 wks. male yes yes Yes DCV+SOF+RBV, 24 wks. REL DCV+SOF, 12 wks. male no yes Yes DCV+SOF+RBV, 24 wks. SVR12 yes Yes LDV+SOF, 24 wks. REL DCV+SOF, 24 wks. male yes male yes yes Yes VEL+SOF+RBV, 24 wks. Pending DCV+SOF, 12 wks. male no yes Yes VEL+SOF+RBV, 24 wks. SVR4 DCV+SOF, 12 wks. male no yes Yes VEL+SOF, 12 wks. REL DCV+SOF, 12 wks. 1 Pt. with VEL failure did not take RBV • Addition of RBV (and treatment extension) may increase SVR rates in patients with baseline RASs and/or cirrhosis • Y93H is commonly observed after DCV/SOF failure, retreatment is challenging Vermehren et al. EASL 2017
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