Feeling right at home

Transcription

1 Feeling right at home

2 Getting to Cure From Cure to Eradication Jordan J. Feld MD MPH Toronto Centre for Liver Disease Sandra Rotman Centre for Global Health University of Toronto

3 SVR Dramatic Improvements % 80% 60% 40% Standard Interferon Ribavirin % Peginterferon % 39% % PR + PI % PR + NI % DAAs % 20% 6% 16% 0% IFN IFN IFN/R IFN/R PegIFN PegIFN/R PR/PI PR/SOF 6 mo 12 mo 6 mo 12 mo 12 mo 12 mo 6-12 mo 3 mo DAAs 3 mo

4 17 HCV Trials in NEJM since 2012

5 Efficacy Very Rapid Progress 1 pill, OD, No AEs, ~% SVR Perfectovir IFN-Free DAA Combos Peg/RBV + BOC/TVR Peg/RBV + 2 nd gen DAA Peg/RBV Tolerability/Safety

6 Efficacy Very Rapid Progress Peg/RBV + BOC/TVR Peg/RBV Tolerability/Safety

7 SVR (%) SVR (%) A Major Advance: G1 Treatment- Naive and Treatment Failures PegIFN + RBV BOC or TVR + PegIFN + RBV PegIFN/RBV BOC or TVR + PegIFN/RBV 0 Relapsers Partial Responders Null Responders Poordad et al NEJM 2011 Jacobson et al NEJM 2011

8 SVR (%) Response to PIs depends on response to IFN Prior relapsers Prior partial responders Prior null responders Pooled T12/PR Pbo/PR n/n= 144/167 12/38 53/62 2/15 48/57 2/15 34/47 3/17 10/18 0/5 11/32 1/5 24/59 1/18 15/38 0/9 7/50 1/10 Stage No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis Zeuzem EASL 2011

9 No free lunch Treatment is more effective but much more difficult

10 Other issues with PI-based therapy Pill Burden Food Requirement Resistance BOC = 18/d TVR = 12/d Drug-Drug Interactions PI CYP3A4 Metabolites

11 Efficacy Very Rapid Progress Peg/RBV + BOC/TVR Peg/RBV + 2 nd gen DAA Protease Inhibitor Nuc Polymerase Inhibitor Peg/RBV Tolerability/Safety

12 SVR12 (%) SVR12 (%) Sofosbuvir + PR G1, 4-6 Naïve (NEUTRINO) SOF 400 mg OD + Peg/RBV x 12 wks / 327 All 206/ / 66 27/ 28 G1a G1b G4 G5* G6* 1/ 1 6/ 6 *not in label AEs similar to Peg/RBV no control arm Lawitz E, et al. NEJM 2013

13 HCV RNA <LLOQ (%) A major advance for patients with cirrhosis No cirrhosis Cirrhosis /273 50/54 269/271 52/54 267/267 53/53 252/273 43/54 Week 2 Week 4 Week 12 Week 12 On treatment Post-treatment Lawitz E, et al. NEJM 2013

14 Summary on Sofosbuvir Pros Once daily Nuc Polymerase Inhibitor Very well tolerated Given for only 12 weeks in ALL patients (no RGT) High SVR even in cirrhosis (80%) Some data in non-g1 High barrier to resistance - no breakthrough only relapse About to be reimbursed (we hope!) Cons Would have been nice to have a control group! No data in treatment experienced naïve only

15 The (many) billion dollar question? Can we get rid of IFN?

16 How many DAAs do we need? Assumptions: 1) Production of new virions = ~10 12 /day 2) HCV genome length = ~9600 nucleotides 3) Error rate = ~10-5 /per nucleotide copied Therefore Average number of changes/genome = 0.096/replication cycle # of nt changes Probability # of virions/d # of all possible mutants % of all possible mutants/d x x x x x x x x10-3 If the theory is right should need 3 DAAs Rong et al Sci Trans Med 2011

17 Not all DAAs are created equal Modeling predicts existence of RAVS, not success of RAVS Genetic barrier Some RAVS less likely to emerge multiple substitutions (eg. 1a vs 1b for PIs/NS5A/NNI) Fitness Not all RAVS created equal S282T for nucs very unfit

18 Fitness Affects Resistance Drug A - Nuc Drug B PI HCV Resistant mutant not so fit (like S282T resistant but unfit) Resistant mutant (like R155K -?slower but still fit)

19 Fitness of Polymerase Inhibitor Mutants Non Nuc Nuc Le Pogam et al JVI 2006 Le Pogam et al JID 2010

20 The HCV Toolbox IFN Challenges Nuc High barrier to resistance RBV NS5A NNI Modest barrier Low barrier PI to resistance to resistance (esp to G1a) (esp to G1a) Treatment Duration Genotype Subtype Cirrhosis Prior Trt/ IL28B Ethnicity BMI HCV RNA

21 The HCV Toolbox IFN Challenges RBV Nuc PI High barrier to resistance Modest barrier to resistance (esp to G1a) Treatment Duration NS5A NNI Low barrier to resistance (esp to G1a) Genotype Subtype Cirrhosis Prior Trt/ IL28B Ethnicity BMI HCV RNA

22 The HCV Toolbox: Mix & Match Nuc RBV NS5A NNI PI Challenges Treatment Duration Genotype Subtype Cirrhosis

23 Can we get rid of IFN? PI NS5A

24 SVR24 (%) PI + NS5A in prior null responders Daclatasvir (NS5A) + asunaprevir (PI) x 24 wks (IFN-Free) US [1] Japan [2] /11 9/10 US Study 9/11 G1a Japanese Study 10/10 G1b Great for G1b not adequate for G1a 1. Lok et al NEJM 2012;366:216-24, 2. Chayama et al, AASLD 2011, oral (LB-4)

25 SVR12 (%) PI + NS5A for G1b relevant for HK Daclatasvir (NS5A) + Asunaprevir (PI) x 24 wks (IFN-Free) in G1b Naive 90 Null/ Partial 82 IFN Ineligible Cirrhosis /10 182/ / / 235 Simple, cheap good for areas with 1b Asia Major caveat: 12% NS5A resistance SVR 40% Reasonable option.but 24 wks 50/ Chayama AASLD 2011, Manns EASL 2014 Abst 0166

26 The HCV Toolbox: The near future If 2 are good, would 3 be better? PI NS5A NNI RBV

27 SAPPHIRE I (naïve) & II (PR failure) 3D + RBV: Co-formulated Paritaprevir(PI)/r/Ombitasvir(NS5A) + Dasabuvir (NNI) = 2 pill OD, 1 pill BID + RBV Week 0 Week 12 Week 24 Week 60 Week 72 N=473 (I) N=297 (II) N=158 (1) N=97 (II) Double-blind Treatment Period 3D+RBV Placebo Primary Analysis: SVR weeks post-treatment follow-up 3D+RBV 48 weeks post-treatment follow-up Open-label Treatment Period No cirrhotics Placebo controlled real assessment of safety

28 SVR12 (%) SVR12 (%) PI + NS5A + NNI + RBV 3D + RBV: Paritaprevir/r (PI) + Ombitasvir (NS5A) + Dasabuvir (NNI) + RBV x 12 wks 96 Naive Treatment Failures (49% nulls) / 473 All Feld J NEJM / 322 G1a 148/ 151 G1b / 297 All 166/ 173 G1a 119/ 123 G1b 5 drugs (3 pills) BUT 12 wks, 1 size fits all Very well tolerated (vs. placebo), few virologic failures Zeuzem S NEJM 2014

29 SVR12, % Patients Feld J EASL 2014 Abst 060, NEJM 2014 When everyone responds N Gender Race BMI IL28B (kg/m 2 ) Genotype Baseline HCV RNA RBV Modification

30 Adverse Events AE, (%) 3D + RBV (N=473) Placebo (N=158) P Value Any AE 87.5* 73.4 <0.05 Fatigue NS Headache NS Nausea 23.7* 13.3 <0.05 Pruritus 16.9* 3.8 <0.05 Hb<10 g/dl 7* 0 <0.05 Bilirubin>3x ULN 5* 0.5 <0.05 DDIs: Similar to first-generation PIs (CYP3A) check the label and other resources (eg, University of Liverpool Web site) Feld J NEJM 2014 Zeuzem S NEJM 2014

31 Is RBV necessary?

32 Ribavirin-Free Therapy in GT1b Wk 12 SVR12, % PEARL-II [1] GT1b Tx Experienced 3 DAAs (n = 95) 3 DAAs + RBV (n = 91) 97 PEARL-III [2] GT1b Tx Naive 3 DAAs (n = 209) 3 DAAs + RBV (n = 210) PEARL-IV [2] GT1a Tx Naive 3 DAAs (n = 205) 3 DAAs + RBV (n = ) RBV needed for GT1a, not necessary for GT1b noncirrhotics 1. Andreone P, Gastroenterology Ferenci P, NEJM 2014

33 TURQUOISE Largest trial of cirrhotics in HCV n=380! Mixed naïve and treatment failures Poordad NEJM 2014

34 SVR12 (%) 3D + RBV in Cirrhosis by G1 Subtype wks 24 wks / 140 G1a 114/ / 68 G1b 12 weeks clearly adequate for G1b What about G1a? 51/ 51 Poordad EASL 2014, LB, NEJM 2014

35 G1a null cirrhotics need 24 SVR12 (%) weeks wks wks / 64 52/ 56 Naive 14/ 15 13/ 13 Relapsers 11/ 11 10/ 10 Partials 40/ 50 Nulls 39/ 42 Suggests that 24 wks optimal for G1a null cirrhotics 12 wks adequate for all others Poordad EASL 2014, LB, NEJM 2014

36 Summary 3D + RBV Highly effective 12 week regimen SVR 96% naïve/experienced Similar G1a (95%) and G1b (98%) Large cirrhotic trial Similar efficacy & safety 12 weeks adequate for all but G1a nulls 24 wks Safety Placebo controlled minimal toxicity Mostly to do with RBV not needed for G1b Resistance Very few breakthroughs 5 in all 3 trials! Relapsers 2 or 3D resistance

37 The HCV Toolbox: The near future Nuc NS5A

38 Sofosbuvir (Nuc) + Daclatasvir (NS5A) Wk 1 Wk 12 Wk 24 SVR12, % n = 15 SOF SOF + DCV HCV GT1 Treatment Naive (N = 126) n = 14 SOF + DCV n = 15 n = 41 SOF + DCV SOF + DCV + RBV n = 41 SOF + DCV + RBV 95 HCV GT1 TVR/BOC Treatment Failures (N = 41) n = 21 SOF + DCV n = 20 SOF + DCV + RBV 95 Sulkowski MS, et al. N Engl J Med. 2014;370:

39 SVR12 (%) How about a single pill? ION 1, 2 & 3: SOF (nuc) + LDV (NS5A) FDC +/- RBV Naïve Prior Trt (incl PI) Failures / 214 S/L 211/ 217 S/L/R 12 wks 212/ 217 S/L 215/ 217 S/L/R 24 wks 102/ 109 S/L 107/ 111 S/L/R 12 wks 108/ 109 S/L 110/ 111 S/L/R 24 wks 202/ wks adequate for non-cirrhotic naïve RBV no benefit No resistance 201/ / 216 S/L S/L/R S/L 8 wks 12 wks Mangia EASL 2014, Afdahl EASL 2014, Kowdley EASL 2014

40 SVR12 (%) SOF/LDV +/- RBV in Cirrhosis 12 Weeks 24 Weeks No cirrhosis Cirrhosis / 87 19/ 22 LDV/SOF 89/ 89 18/ 22 LDV/SOF + RBV 86/ 87 22/ 22 LDV/SOF 88/ 89 22/ 22 LDV/SOF + RBV Cirrhotics need 24 wks of therapy RBV still not helpful Afdahl EASL Abst 0109

41 SVR12 (%) Very effective for prior PI failures 12 Weeks 24 Weeks P/R Failure PI Failure / 43 62/ 66 LDV/SOF 45/ 47 62/ 64 LDV/SOF + RBV 58/ 58 49/ 50 LDV/SOF 58/ 59 51/ 51 LDV/SOF + RBV No cross resistance with PI and either SOF/LDV Afdahl EASL Abst 0109

42 Summary SOF/LDV FDC Very effective single tablet regimen RBV not necessary No difference G1a vs G1b 8 wks adequate for naive, non-cirrhotics May consider extension beyond 12 wks for cirrhotic Very well tolerated No issue with resistance

43 What about G2 and G3?

44 SVR12 (%) SOF + RBV: FISSION (Treatment naïve) SOF + RBV x 12 wks Peg-IFN + RBV x 24 wks /59 44/54 10/11 8/13 89/145 99/139 13/38 11/37 No Cirrhosis Cirrhosis No Cirrhosis GT 2 GT 3 Great for G2 G3 and cirrhosis still a problem Jacobson NEJM 2013 Cirrhosis

45 SVR12 (%) SOF + RBV: FUSION (Treatment Failures) SOF + RBV 12 weeks SOF + RBV 16 weeks /26 23/23 6/10 7/9 14/38 25/40 5/26 14/23 No cirrhosis Cirrhosis 0 No cirrhosis Cirrhosis GT 2 GT 3 Jacobson NEJM 2013 Cirrhosis clearly matters limited data G2 Convincing data for G3 16 is better than 12, what about 24?

46 SVR12 (%) VALENCE SOF + RBV x 24 wks for G No Cirrhosis Cirrhosis wks / 92 Naive 12/ 13 85/ 27/ 45 Treatment Failures 14/ weeks better for naives Not ideal for cirrhotic treatment failures Zeuzem NEJM 2014

47 SVR12 (%) IFN is not quite dead! G3 Treatment Failures Peg/RBV + SOF x 12 wks vs SOF/RBV x 24 wks No Cirrhosis Cirrhosis weeks SOF + PEG/RBV 24 weeks SOF+RBV Peg/RBV + SOF x 12 wks preferable for G3 cirrhosis Esteban EASL 2014

48 A few key conceptual points Not all DAAs are equal even within the same class Barrier to resistance is key Genetic barrier Potency Fitness Extensive intra-class cross resistance remember what they have had before No inter-class cross resistance Likely means even failures will have options

49 Summary Treatment evolving rapidly Options for G1 now BOC/PR x 28 to 48 wks not ideal Peg/RBV + SOF x 12w coming soon Approved IFN-free options very soon 3D (PI + NS5A + NNI) +/- RBV x 12w SOF/LDV (FDC) x 8-12w ASV/DCV x 24 wks G1b (NS5A RAVS) G2 SOF/RBV x 12 wks (?longer for cirrhosis) G3 SOF/RBV x 24 wks vs SOF/Peg/RBV x 12 wks

50 A useful resource Recommendations for Testing, Managing, and Treating Hepatitis C :34 PM Home Full Report Panel Organizations Process Contact Us Recommendations for Testing, Managing, and Treating Hepatitis C Search website What s New and Updates/Changes HCV Guidance Wednesday, January 29, 2014 The Recommendations for Testing, Managing, and Treating Hepatitis C are now available. Read more >> Official Press Release Wednesday, January 29, 2014 View Official Press Release: Online... Read more >> Background of the Hepatitis C Guidance New direct-acting oral agents capable of curing hepatitis C virus (HCV) infection have been approved for use in the United States. The initial direct-acting agents were approved in 2011, and many more oral drugs are expected to be approved in the next few years. As new information is presented at scientific conferences and published in peerreviewed journals, health care practitioners have expressed a need for a credible source of unbiased guidance on how best to treat their patients with HCV infection. To provide healthcare professionals with timely guidance, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) in collaboration with the International Antiviral Society-USA (IAS-USA) have developed a web-based process for the rapid formulation and dissemination of evidence-based, expert-developed recommendations for hepatitis C management. New sections will be added, and the recommendations will be updated on a regular basis as new information becomes available. An ongoing summary of "recent changes" will also be available for readers who want to be directed to / Page 1 of 3

51 A bit confusing now H. pylori But interferon is about to be replaced by a DAA Pak

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