HCV resistance testing in clinical practice. Daniel Bradshaw Virus Reference Department National Infection Service Public Health England

Transcription

1 HCV resistance testing in clinical practice Daniel Bradshaw Virus Reference Department National Infection Service Public Health England

2 Declaration of Interests Dan Bradshaw has received personal grants for research from Janssen and Viiv Pharmaceuticals. 2 HCV resistance testing in clinical practice

3 Overview 1. Introduction 2. Genotypic susceptibility testing 3. Clinical interpretation of resistance mutations 4. Impact of resistance on specific DAA regimens DAA naïve DAA experienced 5. Case study 3 HCV resistance testing in clinical practice

4 1. Introduction 4 HCV resistance testing in clinical practice

5 HCV direct-acting antiviral agents 5 HCV resistance testing in clinical practice

6 Phylogenetic trees for HCV and HIV-1 6 HCV resistance testing in clinical practice Klenerman et al PLoS Med :e

7 % Prevalence of resistance-associated substitutions (RAS), PHE Colindale, Naïve DAA Experienced / / / / /115 NS3 NS5A NS5B /102 7 HCV resistance testing in clinical practice

8 2. Genotypic susceptibility testing 8 HCV resistance testing in clinical practice

9 Sanger Sequencing HCV RNA dntp ddntp DNA polymerase Primer RT-PCR PCR amplification dsdna strand separation cdna PCR amplicon ssdna Primer annealing, dntp incorporation & strand elongation Chain termination with fluorescent ddntp Adapted from Fraher et al Nat Rev Gastroenterol Hepatol 9: Reading of chromatograph & comparison to database

10 Next Generation Sequencing 10 HCV resistance testing in clinical practice Mbisa & Tedder RCPath Bulletin

11 11 HCV resistance testing in clinical practice Clinical interpretation tool

12 Investigation of treatment failure with sequencing 12 HCV resistance testing in clinical practice Midgard et al J Hep 65: S

13 HCV genotype 2k/1b chimeras 13 HCV resistance testing in clinical practice Susser et al J Hep 67:

14 3. Clinical interpretation of RAS 14 HCV resistance testing in clinical practice

15 Clinical interpretation of HCV RAS Viral Genotype / subtype Viral load Fitness Effect in vitro Patient Treatment history Fibrosis stage Regimen Drug potency Genetic barrier to resistance Regimen composition 15 HCV resistance testing in clinical practice

16 Global HCV genotype distribution 16 HCV resistance testing in clinical practice Messina et al Hepatology 61:

17 HCV Genotypes in the UK : different in HIV patients General UK population HIV positive population G1 G4 G3 G1 G2 G3 G4 G1 Slide from G Cooke 17 HCV resistance testing in clinical practice

18 SHARED Study 18 HCV resistance testing in clinical practice Gupta et al EASL PS-090 Paris 2018

19 Prevalence of S282T in patients failing a SOF-containing regimen 19 HCV resistance testing in clinical practice Fourati et al Hepatology doi:

20 Predicted impact of RAS on NS5A inhibitors 20 HCV resistance testing in clinical practice Gottwein et al Gastroenterology154:

21 Clinically important RAS: IDSA / AASLD 2017 Ledipasvir/sofosbuvir Elbasvir/grazoprevir Genotype 1a 1b 3 Q30H/R L31V NA L31M/V Y93H Y93C/H/N M28A/T Y93H NA Q30H/R L31M/V Y93C/H/N Sofosbuvir/velpatasvir NA NA Y93H 21 HCV resistance testing in clinical practice

22 Clinically relevant NS5A resistanceassociated substitutions (RAS) Presentation title - edit in Header and Footer Sorbo et al Drug Resist Update 37:

23 Clinical decision-making No impact Presence of RAS Avoid regimen Prolong therapy Add ribavirin 23 HCV resistance testing in clinical practice

24 o 15 members: PHE HCV Resistance Group Community representative Working document: use of resistance testing to guide therapy o o o o o Epidemiologist Hepatologists ID physicians HIV physicians Virologists Clinical development of GLUE interpretative algorithm Development of collaborative scientific proposals 24 HCV resistance testing in clinical practice

25 4. RAS impact on specific DAA regimens DAA-naïve patients 25 HCV resistance testing in clinical practice

26 100 Efficacy of SOF/LDV in therapy-naive GT1a patients with and without cirrhosis: pooled analysis % SVR weeks 12 weeks ION 1-3 Lonestar 1 Electron / / 365 Nil BL RAS 12 / / 28 BL RAS < 100 FC 24 / / 47 BL RAS > 100 FC Sarrazin et al Gastroenterol 151: HCV resistance testing in clinical practice

27 SVR12 rate (%) UK National Registry: Genotype 1a Non-cirrhotic Treatment Elbasvir-Grazeprevir Number No fibrosis Mild fibrosis Moderate fibrosis of patients: Elbasvir-Grazeprevir and Ribavirin Paritaprevir-Ombitasvir, Dasabuvir Paritaprevir-Ombitasvir, Dasabuvir and Ribavirin Sofosbuvir-Ledipasvir Sofosbuvir-Ledipasvir and Ribavirin Drysdale K, Foster GR et al.. BASL, York, UK Queen Mary University of London

28 SVR12 rate (%) 100 UK National Registry: Genotype 1a Cirrhotic Treatment 95 Elbasvir-Grazeprevir Elbasvir-Grazeprevir and Ribavirin Paritaprevir-Ombitasvir, Dasabuvir Paritaprevir-Ombitasvir, Dasabuvir and Ribavirin Sofosbuvir-Ledipasvir 75 Sofosbuvir-Ledipasvir and Ribavirin 70 Compensated cirrhosis Decompensated cirrhosis Number of patients Drysdale K, Foster GR et al.. BASL, York, UK Queen Mary University of London

29 SVR12 (%) SVR12 in HCV genotype 1a infected patients treated with elbasvir / grazoprevir Any ELB RAS No ELB RAS 20 C-Surfer C-Edge TN C-Edge coinf C-Edge TE C-Worthy C-Salvage 0 441/450 39/56 132/133 11/18 56/56 5/9 67/67 6/6 All 12W no RBV All 12W + RBV 16 or 18W no RBV 16 or 18W + RBV Komatsu et al Gastroenterology 152: HCV resistance testing in clinical practice

30 % SVR Impact of NS5A RAS on SOF/VEL in genotype 3a Astral 1-3, 5 Polaris 2&3 411/420 53/57 19/22 4/6 No RAS Any RAS Y93H Cirrhosis + Y93H Hezode et al J Hep 68: HCV resistance testing in clinical practice

31 % S V R SVR12 for 255 GT1-infected patients with decompensated cirrhosis on SOF/VEL NS5A RAS No NS5A RAS 0 SOF/VEL/RBV 12 SOF/VEL 12 SOF/VEL 24 Astral-4 Curry et al NEJM 373: HCV resistance testing in clinical practice

32 Outcomes of therapy with GLE/PIB in GT3a and NS5A RAS No cirrhosis Cirrhosis %SVR12 Rx naïve Rx exp Rx naïve Rx exp 8 weeks 12 weeks 12 weeks 16 weeks 12 weeks 16 weeks A30K 78 (14/18) 93 (13/14) 25 (1/4) 0 (0/1) 1 (1/1) - No A30K 99 (161/163) 99 (241/243) 96 (43/45) 100 (20/20) 100 (62/62) 94 (48/51) Y93H 100 (10/10) 91 (10/11) 50 (2/4) (5/5) 100 (1/1) No Y93H 97 (165/171) 99 (244/246) 93 (42/45) 95 (20/21) 100 (58/58) 94 (47/50) Surveyor-1,2 Endurance 1-4 Expedition 1 & 4 Krishnan et al AAC pii: HCV resistance testing in clinical practice

33 SVR12 rate (%) UK National Registry: Genotype 3 Non-cirrhotic No fibrosis Mild fibrosis Moderate fibrosis Number of patients Treatment Glecaprevir-Pibrentasvir Sofosbuvir-Velpastasvir Sofosbuvir-Velpatasvir and Ribavirin Sofosbuvir, Daclatasvir Sofosbuvir, Daclatasvir and Ribavirin Drysdale K, Foster GR et al.. BASL, York, UK Queen Mary University of London

34 Resistance testing recommendations: IDSA / AASLD 2017 Regimen GT Rx Hx Elbasvir / grazoprevir 1a TN, TE Sofosbuvir / ledipasvir 1a TE Sofosbuvir / velpatasvir 3 TN (c), TE Sofosbuvir / daclatasvir 3 TN (c), TE 34 HCV resistance testing in clinical practice C cirrhosis, TN treatment naïve, TE (P/R) treatment experienced

35 NHS England rate card (from April 2018) 35 HCV resistance testing in clinical practice Possible role for RAS testing

36 DAA-experienced patients 36 HCV resistance testing in clinical practice

37 12 weeks of sofosbuvir, velpatasvir and voxilaprevir in DAA experienced patients: integrated resistance analysis from phase 3 studies 98% SVR12 NS5A RAS 39% (164/417) NS3+NS5A RAS 18% (76/417) 98% SVR12 282/288 NS3 RAS 12% (48/417) Surveillance of resistance to HCV NS5A inhibitors 37 HCV resistance testing in clinical practice No RAS 31% (129/417) 127/129 POLARIS-1 & POLARIS-4 Deep sequencing with 15% cut off Sarrazin et al THU-248 EASL 2017

38 MAGELLAN-1 Study, Part 2: glecaprevir / pibrentasvir in genotype 1 or 4 with failure to DAA regimen % (77-100) No RASs 100 NS3 only 83 (64-93) NS5A only Breakthrough 1 0 Relapse NS3 + NS5A 38 HCV resistance testing in clinical practice % (77-100) (79-99) No RASs NS3 only NS5A only 25 4 NS3 + NS5A Poordad et al Hepatology 67:

39 Retreatment of HCV infection in patients who failed GLE/PIB with SOF/GLE/PIB + RBV: MAGELLAN-3 study SVR12 (% patients) Arm A, n=2 Arm B, n=21 SVR12 SVR12 Week Treatment arm Cirrhosis Genotype status A 1, 2, 4, 5, 6 NC No B 3 Any Any B Any C Any B Any Any Yes Prior NS5Ai and/or PI* Arm A Arm B Total 39 HCV resistance testing in clinical practice Wyles D, et al, ILC #PS

40 5. Case example 45 year old MSM HIV-1/HCV coinfection Wales CD4 465 (28%) c/mm 3 HIV RNA < 40 c/ml Raltegravir/Truvada HCV genotype 3a HCV RNA 6.1 log IU/mL ALT 131 U/L Fibroscan 12.1 kpa Therapy-naive Nil co-meds Prior IDU nil in 2 years Occasional chems 40 HCV resistance testing in clinical practice

41 Baseline Sanger sequencing Genotype 3a NS5A: A30K 41 HCV resistance testing in clinical practice

42 7 6 GLE/PIB 12 wk post EOT HCV RNA log IU/mL ND Weeks 42 HCV resistance testing in clinical practice

43 Whole genome sequencing Genotype 3a NS3: nil RAS NS5A: A30K + Y93H NS5B: nil RAS 43 HCV resistance testing in clinical practice

44 In vitro fold change in EC50 vs wild type for NS5A RAS in HCV genotype 3a A30K Y93H A30K + Y93H Velpatasvir Pibrentasvir HCV resistance testing in clinical practice 1. Hezode et al J Hep 68: Cheng et al EASL Poster Lawitz et al AAC 60: Krishnan et al AAC doi:

45 Management plan Adherence support? SOF / VEL / VOX +/- RBV? SOF / GLE / PIB +/- RBV 45 HCV resistance testing in clinical practice

46 16 weeks of SOF/GLE/PIB + RBV in genotype 3: Magellan-3 46 HCV resistance testing in clinical practice Lok A, et al. ILC LBO

47 Re-treatment program 5-10%? % DAA virologic failure SOF/VEL/VOX 1 SVR 90-95% SVR 1. NHS retreatment option following nonresponse to any DAA except TPV or BOC next generation sequencing 2 2. HCV Research UK or Public Health England Presentation title - edit in Header and HCV resistance testing in clinical practice Footer

48 Summary RAS testing may be used to support treatment decisions in some circumstances Other treatment strategies without RAS testing often likely to be effective eg where rapid initiation of therapy is critical or no access to RAS testing Key groups for RAS testing: 1. GT1a prior to ELB/GZR 2. GT3a with cirrhosis prior to SOF/VEL 3. All GT with decompensated cirrhosis 4. All rare genotypes and subtypes 5. All GT with NS3 and/or NS5A inhibitor experience prior to re-treatment 48 HCV resistance testing in clinical practice

49 Acknowledgements Antiviral Unit, Virus Reference Department, PHE PHE HCV Resistance Group Tamyo Mbisa David Bibby Carmen Manso Hodan Mohamed Adriana Alvarez Juan Ledesma Renata Piorkowska Yuen Chan Nigel Wallis Ayodele Osobu Laura Bubba Ellie Barnes Will Irving Graham Foster Graham Cooke Anna Maria Geretti David Mutimer Caroline Sabin Brendan Healy Emma Thomson Kosh Agarwal Tamyo Mbisa John McLauchlan Charles Gore Rachel Halford Ras Smit Peter Moss 49 HCV resistance testing in clinical practice

50 SVR4 (%) BACK UP SLIDE Phase 3b study of GLE/PIB ± RBV in GT 1 HCV subjects previously treated with an NS5A inhibitor + SOF therapy Non-cirrhotics (2:1 arm A:B) Cirrhotics (1:1 arm C:D) Arm A Arm B Arm C Arm D GLE/PIB GLE/PIB GLE/PIB + RBV GLE/PIB SVR12 SVR12 SVR12 SVR12 Week Treatment period Post-treatment period Arm C enrollment 86 2 relapse stopped 2/19/18 1 BT 1 relapse 3 BT GLE/PIB x12 weeks GLE/PIB x16 weeks GLE/PIB + RBV x12 weeks GLE/PIB x16 weeks GLE, glecaprevir; PIB, pibrentasvir; RBV, ribavirin; SOF, sofosbuvir; BT, breakthrough Lok A, et al. ILC #LBO HCV resistance testing in clinical practice