Implications of HCV resistance and viral genotypes for the - - PowerPoint PPT Presentation
Implications of HCV resistance and viral genotypes for the - - PowerPoint PPT Presentation
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
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
- 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)
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%)
Typical treatment-emergent RASs
- 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
GT1a GT1b GT2 GT3 GT4
Regimen
NS3 NS5A NS5B NS3 NS5A NS5B NS5A NS5B NS5A NS5B NS3 NS5A NS5B
naive
Q80K # # # # C316N S556G L31M no RASs # no RASs # L30R no RASs
SMV/SOF
(NS3/NS5B)
R155K D168E no RASs D168V L159F C316N not applicaple not applicaple Q80R, D168E no RASs
DCV/SOF
(NS5A/NS5B)
Q30H/R L31M no RASs L31M Y93H L159F C316N no patients Y93H S282T L28M S282T
LDV/SOF
(NS5A/NS5B)
Q30H/R Y93H/N S282T L31M Y93H L159F S282T C316N not applicaple no RASs no RASs L28M Y93C/ H/S S282T
3D/2D
(NS3/NS5A/NS5B)
R155K D168V M28T/V Q30R S556G Y56H D168V Y93H S556G not applicaple not applicaple D168V L28V Y93H
SOF/R
(NS5B)
no RASs L159F C316N no RASs L159F not applicaple
green: 2-20-EC50 fold-change compared to WT replicon
- range: 20-100 fold change
red: >100 fold change # frequencies of natural RASs between 1-20%
Dietz et al. EASL 2016
Italian Study: Multiclass RASs in DAA failures
Di Maio et al. EASL 2017
NS5A inhibitor experienced patients: number of RASs
- Numbers of NS5A RASs were different according to the GT
- Overall 37% (73/198) of NS5A failing individuals had ≥ 2 RASs
n=310 DAA failure pts. n=198 NS5A failure pts.
97% 98% 90% 84% 80% 29%
0% 20% 40% 60% 80% 100%
DAA-naive SOF/PR, SOF/RBV SMV/SOF DCV/SOF LDV/SOF 3D GT1
(Re-)treatable patients without RASs
Theoretical (re)-treatment options according to RASs
Dietz et al. EASL 2016
97% 98% 90% 84% 80% 29% 100%
0% 20% 40% 60% 80% 100%
DAA-naive SOF/PR, SOF/RBV SMV/SOF DCV/SOF LDV/SOF 3D DAA-naive GT1 GT2
(Re-)treatable patients without RASs
Theoretical (re)-treatment options according to RASs
Dietz et al. EASL 2016
97% 98% 90% 84% 80% 29% 100% 100% 95% 16% 95%
0% 20% 40% 60% 80% 100%
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
(Re-)treatable patients without RASs
Theoretical (re)-treatment options according to RASs
Dietz et al. EASL 2016
97% 98% 90% 84% 80% 29% 100% 100% 95% 16% 95% 95% 100% 94% 0%
0% 20% 40% 60% 80% 100%
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
(Re-)treatable patients without RASs
Theoretical (re)-treatment options according to RASs
Dietz et al. EASL 2016
0% 20% 40% 60% 80% 100%
sof/LDV +/- RBV sof + DCV +/- RBV
SVR 12 Initial Treatment Retreatment 46% 50%
n=13 n=2
p<0.05
Real world data (UK): Prolonged retreatment
Cheung et al. EASL 2017
- Virological failure 12 wks NS5A inhibitor/SOF => retreatment 24 wks, same regimen
- All retreated patients had RASs, but 50%
achieved SVR
0% 20% 40% 60% 80% 100%
sof/LDV +/- RBV sof + DCV +/- RBV 12 weeks sof + DCV +/- RBV
SVR 12 Initial Treatment Retreatment
n=45 n=16
69% 63% NS NS
Retreatment GT3
- 70% of DCV (not LDV) treated patients
developed Y93H
- 60% achieved SVR
Retreatment GT1
- Treatment extension can overcome impact of
RASs
- verall n=128 DAA failure pts.
Real world French study: RASs and retreatment
Chevaliez et al. EASL 2017
At the time of retreatment 75% of patients had RASs in NS3 or NS5A
- r NS5B (N=711)
1In total, 9/80 patients were excluded due to failed sequence analysis
100 100 90 88 85 92
20 40 60 80 100 Overall genotype 1 Genotype 1a Genotype 1b No RASs RASs
35 40 17 17 22 26 6 6 12 13 9 10
Virological response to retreatment (N=57)
SVR (%)
- 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
- Initial treatment failure => retreatment using DAA class switch and/or intensified
treatment (+RBV)
Retreatment of Genotype 1 patients
- verall n=159 DAA failure pts.
Real world data (FFM): Rescue according to RASs
n=536 SMV/SOF± RBV n=60 LDV/SOF± RBV n=235 DCV/SOF± RBV n=90 PTV/OBV/±DSV±RBV n=58 SOF/RBV 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 failure, n (%) 43 (77)* 109 (58)* 48 (75)* 27 (67)* 24 (55)* Treatment Duration 8/12/24 wks., n
- /60/-
62/141/32
- /52/38
- /57/1
GT2: 12 wks. GT3: 12-24 wks.
* related to the number of patients with available data
SMV/SOF GT1 Failures LDV/SOF or 3D ±RBV 12/24 wks SVR 28/30 (93%) DCV-/LDV-/SOF GT1 Failures SMV/SOF or 3D ±RBV 12/24 wks SVR 30/33 (91%) 3D GT1 Failures SOF + SMV/LDV ±RBV 12/24 wks SVR 7/7 (100%) SOF/RBV or DCV/SOF GT3 Failures DCV-/LDV-SOF ±RBV 12/24 wks SVR 18/20 (90%) 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)
89% 3% 8% no RASs Y93H A30K
SOF+RBV failures (n=73)
LDV/SOF + RBV (n=1) DCV/SOF ± RBV (n=14) DCV/SOF ± RBV (n=9)
Retreatment with an NS5A-Inhibitor (n=40)
Week 0 12 FU12 24 VEL/SOF + RBV (n=1) VEL/SOF ± RBV (n=15)
89 75 90 100 20 40 60 80 100
DCV/SOF ±RBV LDV/SOF +RBV VEL/SOF ±RBV
SVR (%)
Interim analysis: SVR 88% (n=21/24)
Vermehren et al. EASL 2017 1 pt. with VEL failure did not take RBV
GT3: Optimization of retreatment
Gender Cirrhosis
Prior PEG/R experience
Y93H Retreatment Outcome 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 DCV+SOF, 24 wks. male yes yes Yes LDV+SOF, 24 wks. REL DCV+SOF, 12 wks. 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
Retreatment of GT3 patients who failed a first course of DCV+SOF therapy
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
GT2k/1b: Viral Chimeras
5‘UTR CORE E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B 3‘UTR
GT2k GT1b
UTR – untranslated region, E – envelope protein, NS – non-structural protein, GT - genotype
recombination site: -77 to -73 (relative to strain H77)
GT2k/1b
Target for DAAs
Potential undertreatment
Target for HCV genotyping by sequence analysis
Recombinant virus 2k/1b
Target for HCV genotyping by hybridization assay (LiPATM)
HCV genotype 2
7% 100% 80% 0% 20% 40% 60% 80% 100% SOF/R DCV/SOF LDV/SOF±R 3D
SVR [%] Germany
2/2 4/5 2/2 2/27 100%
- Treatment according to GT2 (SOF/R) is
not sufficient for 2k/1b chimeras
Susser et al. J Hepatol 2017 (accepted)
GT4r: High number of NS5A RASs
Subtype DAA naive (n=117) DAA failure (n=51) 4a 38 (32%) 13 (25%) 4b
- 2 (4%)
4c 1 (1%) 1 (2%) 4d 67 (57%) 19 (37%) 4g 1 (1%)
- 4l
1 (1%)
- 4m
1 (1%)
- 4n
1 (1%) 2 (4%) 4o 1 (1%) 1 (2%) 4r 5 (4%) 12 (24%)* 4v 1 (1%) 1 (2%)
*all 4r patients failed to a NS5A inhibitor regimen
L28M L28V L30H L30R M31L DCV >2-20 (4a) n.d. >100 (4a) >2-20 (4a) >2-20 (4a) LDV 20-100 (4a) n.d. n.d. 20-100 (4a) >2-20 (4a) OBV n.d. 2-20 (4a) >100 (4d) n.d. n.d. active (4d) EBR n.d. n.d. >100 (*) >2-20 (*) >2-20 (*) VEL n.d. n.d. active (4a) >2-20 (4a) n.d.
24% 0% 0% 0% 0% 0% 0% 0% 95% 0% 40% 40% 20% 80% 100%
0% 20% 40% 60% 80% 100%
L28M L28V L30H L30R M31L Frequency of RASs*
subtype 4a (n=38) subtype 4d (n=67) subtype 4r (n=5)
NS5A baseline RASs
DAA-failure DAA-naive
- Intensified treatment should be
considered for GT4r
Conclusions
- High frequencies of treatment-emergent RASs with patterns of RASs according to the
regimen and genotype
- Longer persistence of NS5A RASs
- Retreatment based on RAS analyses with a switch of DAA classes leads to high SVR
rates
- Optimized treatment schedules should be considered in high risk patient groups:
− Individuals with a previous DAA failure − Patients with GT3, baseline RASs and/or cirrhosis (addition of RBV/treatment extension recommended) − 2k/1b chimeras (treatment according to GT2 insufficient) − Subtype 4r (high number of baseline NS5A RASs)
Outlook
- Long-term follow up of RASs in DAA failure patients
- Mechanism of resistance in subtype 4r (structural modelling NS5A RASs)
- Assembly of a cohort of difficult-to-treat patients
- Identification of viral/host risk factors for a virologic failure
- Approval of pan-genotypic regimens awaited (Glecaprevir/Pirbrentasvir;
Voxilaprevir/Velpatasvir/SOF) − Overall high SVR rates in clinical studies achieved, independent of RASs − Virologic failures to rescue treatments mainly had GT3 and RASs − Retreatment of GT3 remains challenging
Acknowledgements
This work is supported by the German Center for Infection Research (DZIF), TTU Hepatitis
University Hospitals: Antoni C, Vogelmann R, Ebert M, Mannheim, Germany Balavoine J & Giostra E, Genf, Switzerland Berg C, Tübingen, Germany Berg T & Böhm S, Leipzig, Germany Buti M, Esteban R, Barcelona,Spain Ciesek S, Essen, Germany De Gottardi A, Bern, Switzerland Dollinger M & Bader, Ulm, Germany Ellenrieder V. & Reinhardt L, Göttingen, Germany Ferenci P, Wien, Austria Gress M, Marburg, Germany Günther R & Wietzke-Braun P., Kiel/Lübeck, Germany Hunyadi B, Kaposvár, Hungary Herrmann A, Stallmach A, Jena, Germany Hoffmann D., München, Germany Klinker H, Würzburg, Germany Lohse A & Schulze zur Wiesch J, von Felden J, Hamburg, Germany Malfertheiner P, Magdeburg, Germany Mayerle J, Raziorrouh B, Munich, Germany Moradpour D, Lausanne, Switzerland Müllhaupt B & Kuntzen T, Zürich, Switzerland Neumann-Haefelin C, Thimme R, Freiburg, Germany Roeb E & Discher T, Gießen, Germany Schattenberg J, Sprinzl M, Galle P, Mainz, Germany Schmidt WE, Bochum, Germany Schmidt H, Münster, Germany Schmiegel W, Bochum, Germany Schott E, Berlin, Germany Siebler J, Erlangen, Germany Spengler U & Rockstroh J, Strassburg C, Bonn, Germany Stauber R., Graz, Austria Strey B., Duisburg, Germany Tomasiewicz K., Lublin, Poland Trautwein C, Tacke F, Aachen, Germany von Hahn T., Cornberg M, Wedemeyer H, Manns M, Hannover, Germany Zachoval R, Munich, Germany Local study sites (private practices): Abels W. & Pfäffl S., Nürnberg, Germany Baermann C., Freiburg , Germany Barth R., Nürnberg, Germany Barthel, K., Leipzig, Germany Bästlein E., Köln, Germany Baumgartl K., Pfungstadt, Germany Beckebaum S, Essen, Germany Börner N., Mainz, Germany Buggisch P. & Petersen J., Hamburg, Germany Busch N., Würselen, Germany Burkhard O. & Reimann B., Worms, Germany Chirca C., Bad Reichenhall, Germany Dienethal A., Frankfurt, Germany Dietel P., Leipzig, Germany Dreher F., Rottenburg, Germany Ehrle U., Pfungstadt, Germany Emke F. & Glosemeyer R., Osnabrück, Germany Felten G. & Hüppe D., Herne, Germany Fischer U., Aalen, Germany Fischer J, München, Germany Frederking D., Hamburg, Germany Frick B., Darmstadt, Germany Gantke B., Düsseldorf, Germany Glaunsinger T., Berlin, Germany Goebel F., München, Germany Göbel U., Cottbus, Germany Heuchel T., Chemnitz, Germany Hinrichsen H., Kiel, Germany Hirschi C., Luzern, Germany Hofmann W.P., Berlin, Germany Holst F., Marburg, Germany Hörster H., Mönchengladbach, Germany John C., Berlin, Germany Jung M. & Zachoval R., München, Germany Kerzel W., Forchheim, Germany Khaykin P., Frankfurt, Germany Klarhof M., Ettlingen, Germany Knapp B, Siegen, Germany Knevels U., Unna, Germany Körfer A., Peine, Germany Künzig, B., Waiblingen, Germany Langenkamp A., Kassel, Germany Littman M., Bad Saulgau, Germany Löhr H., Wiesbaden, Germany Ludwig L., Dornstadt, Germany Lutz T. & Knecht G., Frankfurt, Germany Mainz D., Saarlouis, Germany Maurer P., Bühl, Germany Mauss S., Düsseldorf, Germany Mayer C., Marburg, Germany Moritzen D., Bielefeld, Germany Mroß M., Berlin, Germany Naumann U & Moll A, Berlin, Germany Ningel K., Nürtingen, Germany Obermeier M., Berlin, Germany Oelmann A., Paderborn, Germany Olejnik H. & Gadow K., Goch, Germany Pascher E., Herrieden, Germany Pichler M., Stuttgart, Germany Polzien F., Braunschweig, Germany Raddant R., Geldern, Germany Riedel M., Köln, Germany Schmidtler-von Fabris J., Stadtbergen, Germany Schober A., Göttingen, Germany Schwenzer J., Berlin, Germany Seidel T., Weimar, Germany Seitel G., Karlsruhe, Germany Simon K. & Eisenbach T., Leverkusen, Germany Steffens H., Berlin, Germany Strey B., Duisburg, Germany Tacke W., Königstein, Germany Teuber G., Frankfurt, Germany Teubner K., Stuttgart, Germany Trappe U, Hamm, Germany Ullrich J. & R., Krefeld, Germany Usadel S. , Freiburg, Germany von Lucadou A., Nürnberg, Germany Werheid-Dobers M., Bergisch-Gladbach, Germany Zehnter E., Dortmund, Germany Zipf A., Mannheim, Germany Academic Hospitals: Angeli W., Kempten, Germany Doberauer C., Cologne, Germany Ende K., Erfurt, Germany Erhardt A., Wuppertal, Germany Garrido-Lüneburg A., Bad Oeynhausen, Germany Genné D., Biel, Switzerland Gschwantler M., Wien, Austria Hartmann C., Esslingen, Germany Heyer T., Düren, Germany Kanzler S. Schweinfurt , Germany Kihn R. & Ungemach J., Frankfurt, Germany Kordecki N., Lingen, Germany Kraus M., Altötting-Burghausen, Germany Kullig U., Dresden, Germany Magenta L., Locarno, Switzerland Menges M., Schwäbisch Hall, Germany Niederau C., Oberhausen, Germany Piso J., Olten. Switzerland Reiser M., Marl, Germany Riecken B., Ludwigsburg, Germany Roth J., Lauterbach, Germany Schneider A., Korbach, Germany Schuchmann M., Konstanz, Germany Schulten-Baumer U., Eggenfelden, Germany Seelhoff A., Berlin, Germany Semela D., St. Gallen, Switzerland Stich A., Würzburg, Germany Vollmer C. & Meier A., Augsburg, Germany Walter E., Villingen-Schwenningen Weber A., Nürnberg, Germany Winzer T., Bad Hersfeld, Germany
Liver Centers from Austria, Germany, Hungary, Poland, Spain and Switzerland contributed to this work Christoph Sarrazin Stefan Zeuzem Simone Susser Johannes Vermehren
RASs after NS5A inhibitor failure
Median sampling time point after EOT (mths): DCV/SOF: 3.8 (0.2-19.7) LDV/SOF: 4.7 (0.4-17.1) RASs in DAA-naive pts. (13%) RASs in DCV/SOF pts. (77%) RASs in LDV/SOF pts. (81%)
GT1a – DCV/SOF (n=19), LDV/SOF (n=96)
1% 6% 4% 2% 0% 0% 1% 6% 6% 71% 24% 12% 6% 3% 8% 52% 14% 1% 3% 30%
0% 20% 40% 60% 80% 100% K24N/R M28 A/T/V Q30 E/H/L/K/R L31M/V P32L H58D A92T Y93 C/F/H/N Frequencies of RASs* Q30E/ H/L/K/R Y93C/ F/H/N
EC50 fold change: >100-1000 >100-1000 >1000
L31M/V
GT1b – DCV/SOF (n=14), LDV/SOF (n=96)
Median sampling time point after EOT (mths): DCV/SOF: 3.2 (1.0-18.2) LDV/SOF: 4.0 (0.9-16.1)
<1% 10% 4% 7% 16% 58% 83% 2% 50% 2% 80%
0% 20% 40% 60% 80% 100% R30H L31 F/I/M/V A92T Y93C/H Frequencies of RASs* L31F/ I/M/V Y93 C/H
EC 50 fold change: 2-100 20->1000
RASs in DAA-naive pts. (20%) RASs in DCV/SOF pts. (83%) RASs in LDV/SOF pts. (94%)
GT3 – DCV/SOF (n=53), LDV/SOF (n=20)
7% 2% 15% 2% 66% 5%
0% 20% 40% 60% 80% 100% A30K L31M Y93H Frequencies of RASs* Median sampling time point after EOT (mths): DCV/SOF: 3.8 (0.6-14.7) LDV/SOF: 4.5 (1.4-14.8)
EC 50 fold change: >1000
RASs in DAA-naive pts. (n=436) (9%) RASs in DCV/SOF pts. (n=53) (84%) RASs in LDV/SOF pts. (n=20) (5%)
EOT, end-of-treatment; major increasing RASs are highlighted in red *Double variants were calculated as single RASs. The sum of single RASs is not identical with rate of patients with RASs.
Dietz et al. EASL 2016
RASs after 3D failure
GT1a – 3D (n=32)
median 3.4 mths (0.3-11.6) after EOT
NS3
<1% 1% <1% <1% 2% 1% 42% 5% 47%
0% 20% 40% 60% 80% 100%
F43V Y56H Q80K/R S122R R155K A156 S/TV D168 A/E/N/V
Frequency of RASs*
EC50 10-100 10-100 fold change:
RASs in DAA-naive pts. (3%) RASs in 3D pts (57%)
EC50 >100 fold change: D168 A/E/N/V <1% <1% 35% <1% <1% 1% 16% 38% 22% 44%
0% 20% 40% 60% 80% 100%
F43I Y56H Q80K/R R155 G/K/T A156T/V D168 A/H/E/N/V
Frequency of RASs* RASs in DAA-naive pts. (37%) RASs in 3D pts. (81%)
R155 G/K/T D168 A/E/H/N/V Q80K/R
NS5A GT1b – 3D (n=19)
median 2.9 mths (0.3-7.0) after EOT
<1% 10% 4% 7% 6% 6% 78% R30H L31 F/I/M A92T Y93H
RASs in DAA-naive pts. (20%) RASs in 3D pts. (83%)
20-100 1% 6% 4% 2% <1% <1% 1% 3% 30% 60% 17% K24R M28 A/T/V Q30 E/H/L/R L31M H58D A92T Y93 C/F/H/N
RASs in DAA-naive pts. (13%) RASs in 3D pts. (90%)
50->1000 Q30 E/H/L/R M28 A/T/V
NS5B
38% [WERT] [WERT] 2% 24% 8% 53% 58% C316H/ N S368T M414I Y448H S556G D559N
RASs in DAA-naive pts. (53%) RASs in 3D pts. (68%)
2-20 10-20 C316 H/N 1% 1% 1% 3% 7% 3% 3% 20% 10% C316Y M414I/T Y448C/H G554S S556G/N D559N A553V
RASs in DAA-naive pts. (2%) RASs in 3D pts. (47%)
S556G/N EOT, end-of-treatment; major increasing RASs are highlighted in red *Double variants were calculated as single RASs. The sum of single RASs is not identical with rate of patients with RASs.
Dietz et al. EASL 2016
Italian Study: Multiclass RASs in DAA failures
- 37% of NS5A failing
individuals had ≥ 2 RASs
Di Maio et al. EASL 2017
NS5A inhibitor experienced patients: number of RASs NS5A RASs in patients treated without NS5A inhibitors
- 31% of patients treated without
NS5A inhibitors showed extra- target NS5A RASs (frequently GT1b, GT2)
97% 98% 90% 84% 80% 29% 100% 100% 95% 16% 95% 95% 100% 94% 0%
0% 20% 40% 60% 80% 100%
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
(Re-)treatable patients without RASs
Genotype 1 Genotype 2 Genotype 3 Genotype 4 RASs precluding (re)- treatment NS3 plus NS5A
- r S282T
NS5A
- r S282T
NS5A
- r S282T
NS3 plus NS5A
- r S282T
(Re-)treatment options EBR/GZR LDV/SOF DCV/SOF VEL/SOF 3D DCV/SOF VEL/SOF DCV/SOF VEL/SOF EBR/GZR LDV/SOF DCV/SOF VEL/SOF 2D
Theoretical (re)-treatment options according to RASs
0% 20% 40% 60% 80% 100%
sof/LDV +/- RBV sof + DCV +/- RBV
SVR 12 Initial Treatment Retreatment 46% 50%
n=13 n=2
Frequency of NS5A RAS at retreatment baseline Retreatment baseline(n) % of samples with RAS LDV+DCV (15) 100% p<0.05
Real world data (UK): Prolonged retreatment
Cheung et al. EASL 2017
- Virological failure 12 wks NS5A inhibitor/SOF => retreatment 24 wks, same regimen
- All retreated patients had RASs, but 50% achieved
SVR, GT1l relapsed again
Frequency of NS5A RAS at retreatment baseline Patient Group (n) % samples with Y93H % Y93H treatment emergent LDV retreatment BL (45) 6% 0% DCV retreatment BL (16) 91% 73% 0% 20% 40% 60% 80% 100%
sof/LDV +/- RBV sof + DCV +/- RBV 12 weeks sof + DCV +/- RBV
SVR 12 Initial Treatment Retreatment
n=45 n=16
69% 63% NS NS
Retreatment GT3
- DCV drove Y93H emergence in relapse
- No significant impact of Y93H on SVR
Retreatment GT1
- Treatment extension can overcome impact of RASs
Real world French study: RASs and retreatment
Chevaliez et al. EASL 2017
25.3% 10% 31% 1.4% 22.5% 5.6% 4.2% No RASs NS3 RASs NS5A RASs NS5B RASs NS3+NS5A RASs NS5A+NS5B RASs 3 regions
Resistance profiles at the time of retreatment (N=711)
1In total, 9/80 patients were excluded due to failed sequence analysis
75% of patients with RASs at retreatment 100 100 90 88 85 92
20 40 60 80 100 Overall genotype 1 Genotype 1a Genotype 1b No RASs RASs
35 40 17 17 22 26 6 6 12 13 9 10
Virological response to retreatment (N=57)
SVR (%)
- 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
- Initial treatment failure => retreatment using DAA class switch and/or intensified
treatment (+RBV)
Real world data (FFM): Rescue according to RASs
n=536 SMV/SOF± RBV n=60 LDV/SOF± RBV n=235 DCV/SOF± RBV n=90 PTV/OBV/±DSV±RBV n=58 SOF/RBV n=93 Mean Age (range) 56 (39-75) 57 (28-84) 51 (28-71) 56 (32-79) 54 (27-77) Male gender, n (%) 46 (79) 179 (76) 73 (81) 45 (76%) 74 (80) 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 failure, n (%) 43 (77)* 109 (58)* 48 (75)* 27 (67)* 24 (55)* Treatment Duration 8/12/24 wks., n
- /60/-
62/141/32
- /52/38
- /57/1
GT2: 12 wks. GT3: 12-24 wks.
* related to the number of patients with available data
SMV/SOF GT1 Failures LDV/SOF or 3D ±RBV 12/24 wks SVR 28/30 (93%) DCV-/LDV-/SOF GT1 Failures SMV/SOF or 3D ±RBV 12/24 wks SVR 30/33 (91%) 3D GT1 Failures SOF + SMV/LDV ±RBV 12/24 wks SVR 7/7 (100%) SOF/RBV or DCV/SOF GT3 Failures DCV-/LDV-SOF ±RBV 12/24 wks SVR 18/20 (90%) SVR 2/5 (40%)
Vermehren et al. EASL 2016
Italian Study: Multiclass RASs in DAA failures
Di Maio et al. EASL 2017
- 80% of failure patients showed at least one DAA target RAS
- 40% of NS5A failures had ≥ 2 NS5A RASs
Distribution of NS5A RASs varied according to HCV GT and regimen
GT4r: High number of NS5A RASs
Subtype DAA naive (n=117) DAA failure (n=51) Description of Subtype** 4a 38 (32%) 13 (25%) Egypt 4b
- 2 (4%)
Central Africa 4c 1 (1%) 1 (2%) Central Africa 4d 67 (57%) 19 (37%) Western Europe, Saudi Arabia 4g 1 (1%)
- Central Africa
4l 1 (1%)
- Central Africa
4m 1 (1%)
- Egypt
4n 1 (1%) 2 (4%) Egypt 4o 1 (1%) 1 (2%) Egypt 4r 5 (4%) 12 (24%)* Central Africa 4v 1 (1%) 1 (2%) unassigned
*all 4r patients failed to a NS5A inhibitor regimen
L28M L28V L30H L30R M31L DCV >2-20 (4a) n.d. >100 (4a) >2-20 (4a) >2-20 (4a) LDV 20-100 (4a) n.d. n.d. 20-100 (4a) >2-20 (4a) OBV n.d. 2-20 (4a) >100 (4d) n.d. n.d. active (4d) EBR n.d. n.d. >100 (*) >2-20 (*) >2-20 (*) VEL n.d. n.d. active (4a) >2-20 (4a) n.d.
24% 0% 0% 0% 0% 0% 0% 0% 95% 0% 40% 40% 20% 80% 100%
0% 20% 40% 60% 80% 100%
L28M L28V L30H L30R M31L Frequency of RASs*
subtype 4a (n=38) subtype 4d (n=67) subtype 4r (n=5)
NS5A baseline RASs
**according to Li et al. 2009; Schnell et al. 2015
DAA-failure DAA-naive
- Intensified treatment should be