Virological tools for hepatitis C: re-treatment and resistance. Joop Arends Will Irving. by author

Transcription

1 Virological tools for hepatitis C: re-treatment and resistance Joop Arends Will Irving

2 Disclosures Joop Arends Advisory board: Gilead, Abbvie, Janssen, MSD, BMS (research) grants: Abbvie, BMS, MSD and ViiV Will Irving Advisory board: MSD, Novartis (research) grants: Gilead, Abbvie, Janssen, BMS, Pfizer, GSK

3 Agenda for this morning Warming-up questions to the audience Review of (inter)national guidelines on retreatment Review of clinical trial-data Review of virological methodologies for identifying resistance Data on NHS England Expanded Access programme (decompensated cirrhotics) Case histories for discussion Will and Joop Joop Will Joop and Will

4 Questions for the audience Are DAAs unrestricted reimbursed in your country? Are DAAs reimbursed for DAA treatment failures? Do you perform baseline resistance testing before starting DAA therapy? Do you perform resistance testing after DAA treatment failure?

5 Who should we test for resistance? Nobody? All patients? Selected patients?

6 Review of (inter)national guidelines on retreatment Joop

7 Hepatitis C treatment in 2017

8 Current situation Dutch HIV/HCV database: - 98% SVR - 70% of all patients cured Germany

9 What do the guidelines say? There are 2 important guidelines Static and in pdf Flexible and webbased

10 What to do when relapse occurs? General principles for retreatment a switch of class possible treatment with ribavirine extension of treatment duration NS5A+ NS5B NS5B+ NS3/4A

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13 Review of clinical trial-data Joop

14 What do the data currently tell us? Current registered DAAs Real world data resistance network Vermehren et al. EASL 2016 ASTRAL-1 study QUARTZ-I Phase 2, open-label study of OBV/PTV/r + DSV + SOF ± RBV in DAAexperienced patients with GT1 infection Phase-3: in those previously treated with a DAA plus PEG- IFN/ribavirin, 48 of 48 (100%) achieved SVR Retreatmentwith same regimen after initial short course therapy is successfull C-SWIFT (grazoprevir/elbasvrir) and NIH SYNERGY TRIAL (ledipasvir/sofosbuvir) Gane et al - EASL 2016 (velpatasvir/sofosbuvir)

15 Results vermehren et al.

16 QUARTZ-1 result Overall OBV/PTV/r + DSV + SOF + RBV 12 weeks HCV GT1a No cirrhosis OBV/PTV/r + DSV + SOF + RBV 24 weeks HCV GT1a Cirrhosis OBV/PTV/r + DSV + SOF 12 weeks 77% of patients (17/22) had NS5A RASs at baseline High rate of SVR achieved irrespective of BL RASs

17 Moving into the next generation DAAs

18 3 fixed-dose combinations focussing on prior DAA failures sofosbuvir velpatasvir voxilaprevir MK-3682 grazoprevir ruzasvir glecaprevir pibrentasvir Mean age 58 46% cirrhotics Well tolerated and similar to placebo Bourlière et al. AASLD 2016;

19 3 fixed-dose combinations focussing on prior DAA failures sofosbuvir velpatasvir voxilaprevir MK-3682 grazoprevir ruzasvir glecaprevir pibrentasvir No Impact of Baseline NS5A or NS3 RAVs on SVR4 Treatment was generally safe and welltolerated Wyles et al. AASLD 2016;

20 3 fixed-dose combinations focussing on prior DAA failures sofosbuvir velpatasvir voxilaprevir MK-3682 grazoprevir ruzasvir glecaprevir pibrentasvir Poordad et al. EASL 2017;

21 Virological methodologies for identifying resistance Will

22 Resistance: Principles Monotherapy will result in selection of mutations which enhance replication in presence of drug Darwinian selection Those mutations will come with a fitness cost hence different barriers to resistance BUT - compensatory mutations may improve viral fitness Resistance is NOT all or none hence fold-resistance

23 Resistance: data interpretation Resistance data re difficult to present and difficult to interpret (!) RAS may be Drug specific Genotype specific Sub-genotype specific

24 Gt Gt 1a Gt 1b 3 Lontok et al. Hepatology 2015; 62:

25 Clinically relevant RAV s

26 Resistance: data interpretation Resistance data re difficult to present and difficult to interpret (!) RAS may be Drug specific Genotype specific Sub-genotype specific Fold-resistance? Inherently difficult to determine because of inability to culture HCV Alternative technology e.g. using replicon system Additive effect of multiple mutations? Cross-resistance within-class?

27 Lontok et al. Hepatology 2015; 62:

28 How can we test for the presence of RAS? PCR amplification of target gene(s) and Sanger sequencing Also known as Population sequencing Technically straightforward, may labs capable Will only detect the majority populations Minority species present at <20% will NOT be detected Next generation sequencing Also known as Deep sequencing Provides whole genome sequence (i.e. full length) Can detect minority species down to 1% Technically very exacting, and requires considerable bioinformatics expertise to interpret the data Different possible strategies Metagenomics Pre-selection by target capture

29 Next Gen Sequencing Methods HCV NS5A RNA isolation cdna synthesis Library prepn RAS analysis Metagenomics (VL >10 5 ) Target Enrichment (VL <10 5 ) Quality control Removal of human sequences Viral sequence assembly

30 Are there data to show resistance testing is clinically relevant? Yes in the context of Simeprevir Yes - in the context of Zepatier

31 Resistance associated substitutions (RAS)

32 SIMEPREVIR Guidance For patients with genotype 1a, it is recommended that patients should be tested pre-treatment for the presence of Q80K in NS3.

33 ZEPATIER

34 ZEPATIER

35 ZEPATIER Data sheet for Genotype 1a ZEPATIER for 16 weeks should be considered in patients with baseline HCV RNA level >800K and/or the presence of specific NS5A polymorphisms causing at least a 5-fold reduction in activity of Elbasvir to minimise the risk of treatment failure NHSE guidance For patients with genotype 1a, high viraemia (>800K) it is recommended that patients with NS5A RAV s receive 16 weeks therapy. Other patients should receive 12 weeks treatment

36 NHS England Expanded Access programme Will

37 UK Expanded Access Programme (EAP) Over 800 patients with Child Pugh B cirrhosis or history of decompensation treated in April 2014 September 2016 Upon virological failure, re-treatment with 24 weeks of DAA* was offered Patients were provided with the same regimen, but some accessed alternative therapies *kindly provided by Gilead, Bristol-Myers Squibb & NHS England/ Scotland

38 Resistance Associated Substitutions G1a HCV Research UK AH D-Ia D-Ib LCS-I DCV/LDV binding Posn WT M P Q L P G I P RAS T R I/M D 58 H D D-II 93 Y H/N /S LCS-II D-III 447 Frequency of RAS (consensus level) EAP SVR - baseline 0% EAP Relapser - baseline 21% EAP Relapser post Rx 90%

39 Resistance Associated Substitutions G1a HCV Research UK AH D-Ia D-Ib LCS-I DCV/LDV binding Posn WT M P Q L P G I P RAS T R I/M D 58 H D D-II 93 Y H/N /S LCS-II D-III 447 Frequency of RAS (consensus level) EAP SVR - baseline 0% EAP Relapser - baseline 21% EAP Relapser post Rx 90%

40 HCV Research UK RAS detected in GT3a NS5A at baseline AH D-Ia D-Ib LCS-I DCV/LDV binding Posn GT1a M P A L P G I P NS5A RAS 58 P D-II 93 Y Fold increase in DCV resistance A30S 1 A30K 44 Y93H 2154 LCS-II D-III Most relevant RAS in GT3a resistance 447

41 HCV Research UK RAS detected in GT3a NS5A at baseline and relapse AH D-Ia D-Ib LCS-I DCV/LDV binding Posn GT1a M P A L P G I P D-II Baseline RAS were more frequent in DCV-failures than SVR patients (p<0.05) 58 P 93 Y LCS-II D-III 447 % RAS (baseline) Baseline Relapse SVR 0% - RR LDV 5% 6% RR DCV 11% 85% Filipe et al, unpublished

42 HCV Research UK RAS detected in GT3a NS5A at baseline and relapse AH D-Ia D-Ib LCS-I DCV/LDV binding Posn GT1a M P A L P G I P D-II DCV but not LDV treatment drove development of Y93H after relapse 58 P 93 Y LCS-II D-III 447 % RAS (baseline) Baseline Relapse SVR 0% - RR LDV 5% 6% RR DCV 11% 85% Filipe et al, unpublished

43 EAP Patient Outcomes 583 patients with SVR (82%) 806 patients treated within EAP 711 known virological outcomes 98 patients received retreatment 128 virological failures (18%) 30 declined re-treatment

44 Overall Re-treatment Outcomes 100% 80% 60% 40% 20% 0% SVR G1 (8/16) G2 (1/1) G3 (48/69) G4 (1/1) 58/87 SVR (67%) for patients with known viral outcome -including 2 initial late relapsers after SVR12 29 relapse 6 died 5 lost to follow up * no statistically significant difference between genotypes

45 SVR 12 Genotype 1 Outcome of re-treatment 100% 80% 60% 40% 20% 0% sof/ldv +/- RBV 46% 50% sof + DCV +/- RBV n= 13 n= 2 RAS were present in nearly all relapsed patients therefore does not predict retreatment outcome Frequency of NS5A RAS of interest (present at 15%) Treatment baseline SVR (n=33) 0% Treatment baseline Relapse (n=19) 21% Re-treatment baseline (n=11) 90% G1a RAS at re-treatment baseline: Q30R, L31I, H58P, Y93H/N/S P<0.05

46 Rare Genotype 1 Infections Three patients with G1l HCV all British males from Nigeria All relapsed to 12 weeks Sof + LDV/DCV then to 24 weeks retreatment Baseline NS5A Sequences G---MPRMP Y G---MPRMP Y S---MPQMP Y No known NS5A RAS at relapse NS5A inhibitor Fold increase in EC50 LDV >23,400 DCV >4452 VEL 198 HCV Research UK

47 SVR 12 Genotype 3 Impact of RAS on re-treatment 100% 80% 60% 40% 20% 0% All RAS + RAS - NS LDV/LDV NS 69% 71% 72% 63% 70% 50% DCV/DCV RAS at re-treatment baseline Y93H A30K/S L31M RAS were frequent following relapse but did not impact on retreatment outcome HCV Research UK

48 Who should we test for RAVs? Nobody? All patients? Selected patients? Genotype 1a for Simprevir/Zepatier? Previously treated with Telaprevir/Boceprevir/Simeprevir? Failed DAA therapy? But bear in mind other reasons for treatment failure: Not enough drug compliance? Duration of therapy? Rare subtypes inherently resistant eg Gt 1l Error in genotyping due to recombinant virus

49 Recombinant HCV

50 Who should we test for RAVs? Nobody? All patients? Selected patients? Genotype 1a for Simprevir/Zepatier? Previously treated with Telaprevir/Boceprevir/Simeprevir? Failed DAA therapy? But bear in mind other reasons for treatment failure: Not enough drug compliance? Duration of therapy? Rare subtypes inherently resistant eg Gt 1l Error in genotyping due to recombinant virus What do the guidelines advise us to do?

51 What do the guidelines advise? (1) AASLD Guidelines Testing for the presence of resistance-associated variants (RAV) prior to starting treatment should be performed as recommended in the Initial Treatment and the Retreatment Sections: (Class IIb, Level B) Genotype 1a For those patients whose prior treatment regimen containing an NS5A inhibitor failed and who have cirrhosis or require urgent retreatment treatment-naïve or PEGIFN/ribavirin-experienced persons with genotype 1a HCV who are being treated with elbasvir/grazoprevir. testing for the Q80K NS3 RAV is recommended when simeprevir and sofosbuvir are being considered as treatment Genotype 3 NS5A RAV testing is also recommended in persons with genotype 3 HCV who are considering treatment with sofosbuvir/velpatasvir or daclatasvir/sofosbuvir-based regimens. The Y93H variant being most problematic.

52 What do the guidelines advise? (2) EASL Guidelines Systematic testing for HCV resistance prior to treatment is NOT recommended. (B1). The utility of HCV resistance testing prior to retreatment in patients who failed on any of the DAA-containing treatment regimens is UNKNOWN. Physicians who have easy access to a reliable test assessing HCV resistance to NS5A inhibitors can use these results to guide their decisions The test should be based on population sequencing (reporting RASs as present or absent ) or deep sequencing with a cut-off of 15% (only RASs that are present in more than 15% of the sequences generated must be considered) (B1).

53 Clinical cases Joop and Will

54 Case 1 56 year old male HCV genotype 4 ; fibroscan F1F2 ; HCV RNA 6,4 x 10^6 IU/ml 2002 PEG/ RBV stop because of non-response 2015 sofosbuvir/ simeprevir 12 weken waarna virologische relapse What do the guidelines say?

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56 Case 2 A 50 year old patient HCV GT1a with viral load 8x10E5 IU/ml F0F1 on fibroscan Prior treatment with ledipasvir/sofosbuvir HCV genotyping showed NS5A resistance mutations (Y93H and L31M) no NS3 resistance mutations What would you advise as new treatment?

57 My advice for treatment would be a) Paritaprevir/r, ombitasvir, dasabuvir +/- ribavirin b) Paritaprevir/r, ombitasvir, dasabuvir + sofosbuvir +/- ribavirin c) Grazoprevir/ elbasvir +/- ribavirin d) Grazoprevir/ elbasvir + sofosbuvir +/- ribavirin e) Wait for next generation DAAs in 2018

58 What does the EASL guideline say?

59 Case 3 Female 55 years old HCV genotype 3a fibroscan 14,2 kpa (F3/F4) Sept 2015 referral for treatment after previous virological relapse after 12 weeks sofosbuvir/ daclatasvir How to proceed? Genotypic resistance: Y93H mutation in NS5A

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61 Phase-2 re-treatment study with SOF/VEL/RBV 24 weeks in prior failures Gane ea EASL 2016

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63 Case 3 Female 55 years old HCV genotype 3a fibroscan 14,2 kpa (F3/F4) Sept 2015 referral for treatment after previous virological relapse after 12 weeks sofosbuvir/ daclatasvir How to proceed? Genotypic resistance: Y93H mutation in NS5A Your advice? Based on 13 patients treated with SOF/VEL/RBV 24 weeks? Await future options?

64 Thank you for your attention questions?