Feeling right at home Getting to Cure From Cure to Eradication - - PowerPoint PPT Presentation

Feeling right at home

From Cure to Eradication

Jordan J. Feld MD MPH

Toronto Centre for Liver Disease Sandra Rotman Centre for Global Health University of Toronto

Getting to Cure

0% 20% 40% 60% 80% 100%

IFN IFN IFN/R IFN/R PegIFN PegIFN/R

SVR

16% 55% 6% 34% 42% 39%

6 mo 12 mo 6 mo 12 mo 12 mo

1991 1995 1998 2002 2001

Ribavirin Peginterferon Standard Interferon

6-12 mo

75% 2011

PR + PI

PR/PI 12 mo 3 mo

90% 2013

PR + NI

PR/SOF

Dramatic Improvements

3 mo

95-99%

2014

DAAs

DAAs

17 HCV Trials in NEJM since 2012

Very Rapid Progress

Efficacy Peg/RBV

Peg/RBV + BOC/TVR

Peg/RBV + 2nd gen DAA

IFN-Free DAA Combos

1 pill, OD, No AEs, ~100% SVR

Perfectovir Tolerability/Safety

Very Rapid Progress

Efficacy Peg/RBV

Peg/RBV + BOC/TVR

Tolerability/Safety

A Major Advance: G1 Treatment- Naive and Treatment Failures

20 40 60 80 100 SVR (%) PegIFN/RBV BOC or TVR + PegIFN/RBV 38-44 63-75 Poordad et al NEJM 2011 Jacobson et al NEJM 2011 20 40 60 80 100 SVR (%) Relapsers Partial Responders 69-83 PegIFN + RBV Null Responders BOC or TVR + PegIFN + RBV 24-29 40-59 7-15 29-40 5

Response to PIs depends on response to IFN

Prior relapsers Prior partial responders Prior null responders

86 85 84 72 56 34 41 39 14 32 13 13 18 20 6 10

20 40 60 80 100

2/15

n/N=

53/62 144/167 12/38 0/5 10/18 34/47 3/17 0/9 15/38 11/32 1/5

No, minimal

• r portal

fibrosis Cirrhosis Stage

Pooled T12/PR48 Pbo/PR48

SVR (%)

2/15 48/57 24/59 1/18 7/50 1/10

Bridging fibrosis No, minimal

• r portal

fibrosis Cirrhosis Bridging fibrosis No, minimal

• r portal

fibrosis Cirrhosis Bridging fibrosis

Zeuzem EASL 2011

No free lunch

Treatment is more effective but much more difficult

Other issues with PI-based therapy

BOC = 18/d TVR = 12/d

Pill Burden Food Requirement CYP3A4 PI Metabolites Drug-Drug Interactions Resistance

Very Rapid Progress

Efficacy Peg/RBV

Peg/RBV + BOC/TVR

Peg/RBV + 2nd gen DAA

Tolerability/Safety

Protease Inhibitor Nuc Polymerase Inhibitor

Sofosbuvir + PR G1, 4-6 Naïve

(NEUTRINO)

100 80 60 40 20

SVR12 (%)

90

295/ 327

All 92

206/ 225 SVR12 (%)

82

54/ 66

96

27/ 28

100

1/ 1

100

6/ 6

G1a G1b G4 G5* G6*

*not in label

SOF 400 mg OD + Peg/RBV x 12 wks

Lawitz E, et al. NEJM 2013

AEs similar to Peg/RBV  no control arm

A major advance for patients with cirrhosis

91 93 99 96 100 100 92 80 20 40 60 80 100

No cirrhosis Cirrhosis

Post-treatment On treatment HCV RNA <LLOQ (%)

50/54 52/54 53/53

Week 2 Week 4 Week 12 Week 12

43/54 249/273 269/271 267/267 252/273

Lawitz E, et al. NEJM 2013

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

The (many) billion dollar question?

Can we get rid of IFN?

How many DAAs do we need?

Assumptions: 1) Production of new virions = ~1012/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 0.91 9.1 x 1011 1 0.087 8.7 x 1010 2.9 x 104 100 2 0.0042 4.2 x 109 4.1 x 108 100 3 0.00013 1.3 x 108 1.0 x 1012 3.4x10-3

If the theory is right – should need 3 DAAs

Rong et al Sci Trans Med 2011

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

Fitness Affects Resistance

Drug A - Nuc Drug B – PI Resistant mutant…not so fit (like S282T – resistant but unfit) Resistant mutant… (like R155K - ?slower but still fit) HCV

Fitness of Polymerase Inhibitor Mutants

Non Nuc Nuc

Le Pogam et al JVI 2006 Le Pogam et al JID 2010

The HCV Toolbox

IFN Genotype Subtype Cirrhosis

Challenges

Prior Trt/ IL28B

BMI Ethnicity HCV RNA Treatment Duration Nuc Nuc High barrier to resistance Nuc RBV NS5A NNI Low barrier to resistance (esp to G1a) NS5A NNI PI Modest barrier to resistance (esp to G1a) PI PI

The HCV Toolbox

IFN Genotype Subtype Cirrhosis

Challenges

Prior Trt/ IL28B

BMI Ethnicity HCV RNA Treatment Duration PI Nuc Modest barrier to resistance (esp to G1a) High barrier to resistance NS5A NNI Low barrier to resistance (esp to G1a) NS5A Nuc Nuc PI NNI PI RBV

The HCV Toolbox: Mix & Match

Genotype Subtype Cirrhosis

Challenges

Treatment Duration RBV PI Nuc NS5A NNI NS5A Nuc Nuc RBV PI NNI PI RBV NS5A

Can we get rid of IFN?

PI NS5A

PI + NS5A in prior null responders

100 80 60 40 20 36

Daclatasvir (NS5A) + asunaprevir (PI) x 24 wks (IFN-Free)

SVR24 (%) US [1] 90 Japan [2] 9/10 4/11

• 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)

US Study 9/11 G1a Japanese Study 10/10 G1b

PI + NS5A for G1b – relevant for HK

100 80 60 40 20

Daclatasvir (NS5A) + Asunaprevir (PI) x 24 wks (IFN-Free) in G1b

SVR12 (%) 90 9/10

• Simple, cheap  good for areas with 1b  Asia
• Major caveat: 12% NS5A resistance  SVR 40%
• Reasonable option….but 24 wks…
• 1. Chayama AASLD 2011, Manns EASL 2014 Abst 0166



90 182/ 203 82 168/ 205 82 192/ 235

Naive Null/ Partial IFN Ineligible

50/ 68 73

Cirrhosis

The HCV Toolbox: The near future

RBV PI NS5A NNI

If 2 are good, would 3 be better?

N=473 (I) N=297 (II) N=158 (1) N=97 (II) Primary Analysis: SVR12 Double-blind Treatment Period Open-label Treatment Period

48 weeks post-treatment follow-up 48 weeks post-treatment follow-up

3D+RBV Placebo 3D+RBV

Week 0 Week 12 Week 24 Week 60 Week 72

3D + RBV: Co-formulated Paritaprevir(PI)/r/Ombitasvir(NS5A) + Dasabuvir (NNI) = 2 pill OD, 1 pill BID + RBV

SAPPHIRE I (naïve) & II (PR failure)

• No cirrhotics
• Placebo controlled  real assessment of safety

PI + NS5A + NNI + RBV

3D + RBV: Paritaprevir/r (PI) + Ombitasvir (NS5A) + Dasabuvir (NNI) + RBV x 12 wks

Feld J NEJM 2014 100 80 60 40 20 SVR12 (%) 95

307/ 322

G1a

98

148/ 151

96

455/ 473

All G1b

Naive

100 80 60 40 20 SVR12 (%) 96

166/ 173

G1a

97

119/ 123

96

286/ 297

All G1b

Treatment Failures (49% nulls)

• 5 drugs (3 pills) BUT 12 wks, 1 size fits all
• Very well tolerated (vs. placebo), few virologic failures

Zeuzem S NEJM 2014

When everyone responds…

Gender Race IL28B Genotype Baseline HCV RNA RBV Modification 25 50 75 100

SVR12, % Patients

95.2 97.5 96.4 96.2 96.5 96.0 93.5 96.4 271 202 28 445 144 329 31 442

N

98.1 95.7 104 369

BMI (kg/m2)

402 71 97.0 91.5

Feld J EASL 2014 Abst 060, NEJM 2014

Adverse Events

AE, (%) 3D + RBV (N=473) Placebo (N=158) P Value Any AE 87.5* 73.4 <0.05 Fatigue 34.7 28.5 NS Headache 33.0 26.6 NS Nausea 23.7* 13.3 <0.05 Pruritus 16.9* 3.8 <0.05 Hb<10 g/dL 7* <0.05 Bilirubin>3x ULN 5* 0.5 <0.05

Feld J NEJM 2014 Zeuzem S NEJM 2014

• DDIs: Similar to first-generation PIs (CYP3A)  check the label and
• ther resources (eg, University of Liverpool Web site)

Is RBV necessary?

Ribavirin-Free Therapy in GT1b

GT1b Tx Naive

99 99

PEARL-III[2]

• 1. Andreone P, Gastroenterology. 2014
• 2. Ferenci P, NEJM 2014

3 DAAs + RBV (n = 91) 3 DAAs (n = 95) GT1b Tx Experienced

Wk 12 100 97 SVR12, %

PEARL-II[1] GT1a Tx Naive

90 97

PEARL-IV[2] 3 DAAs + RBV (n = 210) 3 DAAs (n = 209) 3 DAAs + RBV (n = 100) 3 DAAs (n = 205)

• RBV needed for GT1a, not necessary for GT1b noncirrhotics

TURQUOISE

• Largest trial of cirrhotics in HCV – n=380!
• Mixed naïve and treatment failures

Poordad NEJM 2014

3D + RBV in Cirrhosis by G1 Subtype

100 80 60 40 20 SVR12 (%)

94

114/ 121

89

120/ 140

G1a

51/ 51 67/ 68

100 99

G1b

24 wks 12 wks

• 12 weeks clearly adequate for G1b
• What about G1a?

Poordad EASL 2014, LB, NEJM 2014

G1a null cirrhotics need 24 weeks…

100 80 60 40 20 SVR12 (%)

93

52/ 56

93

59/ 64

Naive

100

13/ 13

93

14/ 15

Relapsers

100

10/ 10

100

11/ 11

Partials

93

39/ 42

80

40/ 50

Nulls

• Suggests that 24 wks optimal for G1a null cirrhotics
• 12 wks adequate for all others

24 wks 12 wks

Poordad EASL 2014, LB, NEJM 2014

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

The HCV Toolbox: The near future

NS5A Nuc

Sofosbuvir (Nuc) + Daclatasvir (NS5A)

Sulkowski MS, et al. N Engl J Med. 2014;370:211-221.

HCV GT1 TVR/BOC Treatment Failures (N = 41) HCV GT1 Treatment Naive (N = 126)

SOF + DCV SOF + DCV + RBV

SVR12, % 100

SOF

n = 15

SOF + DCV

n = 14 100 100 n = 15

SOF + DCV SOF + DCV + RBV

n = 41 n = 41 100 95

SOF + DCV + RBV SOF + DCV

n = 21 100 95 n = 20

Wk 12 Wk 24 Wk 1

How about a single pill?

Naïve

100 80 60 40 20 SVR12 (%) 99

211/ 214

97

211/ 217

S/L S/L/R

12 wks

Prior Trt (incl PI) Failures

94

102/ 109

S/L

107/ 111

96

S/L/R

12 wks ION 1, 2 & 3: SOF (nuc) + LDV (NS5A) FDC +/- RBV

108/ 109

99

S/L

24 wks

110/ 111

99

S/L/R

94

202/ 215

93

201/ 216

95

8 wks 12 wks

S/L S/L/R S/L

206/ 216

Mangia EASL 2014, Afdahl EASL 2014, Kowdley EASL 2014

• 8 wks adequate for non-cirrhotic naïve
• RBV no benefit
• No resistance

98

212/ 217

99

215/ 217

S/L S/L/R

24 wks

SOF/LDV +/- RBV in Cirrhosis

No cirrhosis Cirrhosis

83/ 87 19/ 22 89/ 89 18/ 22 86/ 87 22/ 22 88/ 89 22/ 22

12 Weeks 24 Weeks

LDV/SOF + RBV LDV/SOF + RBV LDV/SOF LDV/SOF SVR12 (%)

100 80 60 40 20

95 86 100 82 100 99 100 99

• Cirrhotics need 24 wks of therapy
• RBV still not helpful

Afdahl EASL Abst 0109

Very effective for prior PI failures

P/R Failure PI Failure

40/ 43 62/ 66 45/ 47 62/ 64 58/ 58 49/ 50 58/ 59 51/ 51

12 Weeks 24 Weeks

LDV/SOF + RBV LDV/SOF + RBV LDV/SOF LDV/SOF SVR12 (%)

100 80 60 40 20

93 94 96 97 100 98 98 100

• No cross resistance with PI and either SOF/LDV

Afdahl EASL Abst 0109

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

What about G2 and G3?

98 82 91 62 61 71 34 30 20 40 60 80 100

SOF + RBV x 12 wks Peg-IFN + RBV x 24 wks

GT 2 GT 3

SVR12 (%)

No Cirrhosis No Cirrhosis Cirrhosis Cirrhosis

SOF + RBV: FISSION (Treatment naïve)

58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37

• Great for G2
• G3 and cirrhosis still a problem

Jacobson NEJM 2013

96 100 60 78 20 40 60 80 100 37 63 19 61 20 40 60 80 100

6/10 5/26

SOF + RBV: FUSION (Treatment Failures)

SVR12 (%)

25/26 7/9 23/23 14/38 14/23 25/40

No cirrhosis

SOF + RBV 12 weeks SOF + RBV 16 weeks

No cirrhosis Cirrhosis Cirrhosis

GT 2 GT 3

• Cirrhosis clearly matters  limited data G2
• Convincing data for G3
• 16 is better than 12, what about 24?

Jacobson NEJM 2013

VALENCE

100 80 60 40 20 SVR12 (%) 93

86/ 92

85

85/ 100

Naive Treatment Failures

SOF + RBV x 24 wks for G3

• 24 weeks better for naives
• Not ideal for cirrhotic treatment failures

Zeuzem NEJM 2014

92

12/ 13

60

27/ 45

No Cirrhosis Cirrhosis

61

14/ 23

16 wks

IFN is not quite dead!

93 74 88 47 20 40 60 80 100 12 weeks SOF + PEG/RBV 24 weeks SOF+RBV SVR12 (%)

No Cirrhosis Cirrhosis Peg/RBV + SOF x 12 wks preferable for G3 cirrhosis

Esteban EASL 2014

G3 Treatment Failures Peg/RBV + SOF x 12 wks vs SOF/RBV x 24 wks

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

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

A useful resource

Recommendations for Testing, Managing, and Treating Hepatitis C

Background of the Hepatitis C Guidance

• available. An ongoing summary of "recent changes" will

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 >>

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www.hcvguidelines.org

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