9/28/2018

1

Best Practices: Treatment of

Genotype 1

Hemant Shah MD MScCH HPTE

Jordan Feld MD MPH

Disclosures

Dr Shah

• Consulting Fees: Abbvie, Gilead, Merck,

Intercept, Lupin

Dr. Feld

• Research: Abbott, Abbvie, Gilead, Janssen,

Merck

• Consulting: Abbvie, Gilead, Merck

Learning Objectives1. Recognize the various treatment options for genotype 1

HCV infection

2. Understand the pros and cons of the approved regimens for genotype 1 HCV infection

3. Develop a strategy for choosing the right regimen for the right patient

4. Describe the treatment options for patients with Genotype 1 infection

5. Analyze the major trials data

6. Apply data to patient profiles

Public Reimbursement Rules

• Treatment Naïve Patients: No restrictions

• Treatment Experienced Patients: No restrictions

• Retreatment due to reinfection – case by case

Ontario Drug Benefit Program – March 1 2018

Genotype 1

• The most common worldwide

– 70% of all HCV infections including in Canada

• Most difficult to cure with interferon-based therapy (40% SVR with 48 weeks of therapy!)

• 2 major subtypes – 1a and 1b

– Important differences in terms of response to certain classes of drugs

– In Canada – 1a = 2/3 and 1b = 1/3 of G1 infections

• All direct-acting antivirals initially designed for genotype 1!

Centre for Disease Analysis 2014

G1 in Canada

Centre for Disease Analysis 2014

9/28/2018

2

The Lifecycle - Lots of Targets

Manns Nat Rev 2007

ProteaseInhibitors-previr

PolymeraseInhibitors-buvir

NS5AInhibitors- asvir

Funded Regimens on Limited

UseGenotype Regimen Duration(s)

1a/b SOF/LDV 8,12,24

SOF/LDV + RBV 12

SOF/VEL 12

SOF/VEL + RBV 12

GZP/EBV 8,12

GZP/EBV + RBV 16

1b ASV/DCV 24

NOT FUNDED 1a/1b GLE/PIB 8,12

Lots of options…how do you

choose the right one?

• The good news is they all work very well!!

• SVR rates consistently >95% in clinical trials and

real-world studies

• Safety/tolerability excellent

• For most patients, any of the options are fine

Choosing a regimen• A few things to know:

1. Fibrosis assessment

– Cirrhosis?

– If yes – any history or signs of decompensation

2. Genotype 1 subtype

3. Treatment history

– Regimen + duration

– Resistance testing

4. Co-morbidities

– Con-meds

Why does sub-type matter?G1b – EASY to cure

• No need for resistance

testing – no effect

• No need for RBV

• Protease-based regimens

highly effective

G1a – Tougher to cure

• Resistance testing for some

patients

• RBV needed for some

patients with some regimens

• Protease-based regimens a

bit less effective

Great options for G1

3 questions (or maybe just 2)

1. Does the patient have cirrhosis?

2. G1 subtype?

3. Naïve or experienced (and with what)?

9/28/2018

3

Great options for G1

Does the patient have cirrhosis?

No don’t need to ask question 3 – regimens just about the same for naïve and experienced

Naïve/Experienced

SOF/LDV x (8-)12w

GLE/PIB x 8-12w

SOF/LDV x (8-)12w

Naïve/Experienced

1b 1a

SOF/VEL x 12w SOF/VEL x 12w

EBV/GZV x (8-)12w EBV/GZV x 12w

GLE/PIB x 8-12w

Great options for G1

Does the patient have cirrhosis?

Yes – now question 3 (naïve/experienced) matters

Naive

1b

SOF/LDV x 12w

1a

SOF/LDV x 12w

Naive ExperiencedExperienced

24w or + RBV x 12w 24w or + RBV x 12w

Don’t use

No change

No change

No change

SOF/VEL x 12w No change

GZV/EBV x 12w No change GZV/EBV x 12w 16w NRs

GLE/PIB x 8-12w GLE/PIB x 8-12w

SOF/LDV (Harvoni) or SOF/VEL (Epclusa)

• Single Tablet Regimen

• Well tolerated– Fatigue, headache common, occasionally severe

– Some patients complain more than expected

• SOF/LDV (not SOF/VEL) – can shorten to 8 weeks if HCV RNA<6 M IU/ML

• DDIs – NS5A adds some– Acid Suppression: Reduce absorption up to 80%!

• PPI – best to avoid (can co-administer)

• Antacid – 4 hrs apart

• H2RA – 12 hrs apart or together

– Seizure meds: All seizure meds except Kepra

– HBV/HIV - tenofovir – increase levels (renal toxicity)

– Cardiac: Digoxin – avoid

Crestor - increase risk of rhabdo – usually stop it

SVR12 by Genotype

ASTRAL-1: SOF/VEL STR for 12 Weeks in GT 1, 2, 4, 5, 6 HCV-Infected Patients

Feld, AASLD, 2015, LB-2. Feld JJ, et al. N Engl J Med. 2015. DOI: 10.1056/NEJMoa1512610

99 98 99 100 100 97 100

0

20

40

60

80

100

SVR

12

(%

)

618/624

Total

206/210 117/118 104/104 116/116 34/35 41/41

1a 1b 2 4 5 6

GenotypeLTFU=lost to follow up; WC=withdrew consent

‡

SOF/LDV (Harvoni) or SOF/VEL (Epclusa)

• Single Tablet Regimen

• Well tolerated– Fatigue, headache common, occasionally severe

– Some patients complain more than expected

• SOF/LDV (not SOF/VEL) – can shorten to 8 weeks if HCV RNA<6 M IU/ML

• DDIs – NS5A adds some– Acid Suppression: Reduce absorption up to 80%!

• PPI – best to avoid (can co-administer)

• Antacid – 4 hrs apart

• H2RA – 12 hrs apart or together

– Seizure meds: All seizure meds except Kepra

– HBV/HIV - tenofovir – increase levels (renal toxicity)

– Cardiac: Digoxin – avoid

Crestor - increase risk of rhabdo – usually stop it

Elbasvir/Grazoprevir (Zepatier) • Single Tablet Regimen

• Well tolerated– Fatigue, headache

– Cannot be used in decompensated cirrhosis

• Resistance an issue with G1a (not with G1b)– If present extend to 16 weeks and add RBV

– Either test everyone (guidelines) or Treat naïve/relapsers x 12w & non-responders for 16 weeks with RBV (Label)

• DDIs – protease adds some

- No PPI issue

- Limited Amio issue

- Safe in renal failure including dialysis

- Look up the others…

9/28/2018

4

Experience with Elbasvir/Grazoprevir in the Veterans

Affairs Healthcare System

* SVR12 was available for 81% of the patients. If these data were not available, SVR was defined based on HCV RNA test available from week 4 to 12 weeks after the end of treatment.** Evaluable population: All patients who had HCV RNA test available at 4 weeks or more post treatment, including patients who received EBR/GZR < 11 weeks of treatment.

† Per protocol: Patients who completed treatment course and had virologic outcomes at 4 weeks or more post-treatment.Puenpatoom A, et al. Presented at EASL 2017; Presentation #PS-095.

• Subjects: 2,436 patients with HCV treated with EBR/GRZ in the VA

healthcare system (USA)

• Predominantly GT1: GT1a (36%); GT1b (62%)

• Baseline CKD3-5: 33%

• Cirrhotic: 33%

• Other comorbidities:

• History of drug abuse (54%); history of alcohol abuse (61%); diabetes (53%); depression (57%); HIV (3%)

96% 97%

0%

20%

40%

60%

80%

100%

Evaluablepopulation**

Per protocolpopulation†

SVR* Overall

2328 /2436

2190 /2257

93% 97% 96% 93% 96% 96% 95% 96%

GT1a GT1b Tx-naïve

Tx-experienced

Cirrhosis CKDStage 4-5

Hx ofdrug abuse

African-American

SVR* in Subgroups (Evaluable Population)

788/844

1379/1428

1910/1988

418/448

772/808

1251/1313

392/407

1342/1400

This is part of the EASL 2017 slide kit which must be presented as a whole

Pibrentasvir/Glecaprevir

(Maviret) • Three Tablets Taken all at once

• Well tolerated– Fatigue, headache

– Cannot be used in decompensated cirrhosis

• No issues with resistance to date

• For non-cirrhotic patients – 8 weeks

• For cirrhotic patients – 12 weeks

• Can be used in some patients who have failed prior DAA therapy, but not preferred

• DDIs – protease adds some

- No PPI issue

- Limited Amio issue

- Safe in renal failure including dialysis

- Look up the others…

Integrated Efficacy Analysis of 8 and 12 Weeks of G/P in

HCV Genotype 1–6 Infected Patients without Cirrhosis (Efficacy

ITT)

• Puoti M, et al. J Hepatol 2017; 66:S721 (poster presentation SAT-233).

• ITT, intent-to-treat.

• * All GT3 patients were treatment-naïve; † Patient missing SVR data returned after • post-treatment week 12 and had achieved HCV RNA <lower limit of quantification.

97 99 98 95 93100

9099 99.8 99 96 99 100 100

0

20

40

60

80

100

Overall GT1 GT2 GT3* GT4 GT5 GT6

SVR

12

, ITT

(%

)

8 week G/P 12 week G/P

383387

400401

193197

232234

177186

258270

4346

111112

22

2828

9†

103131

807828

10601076

nN

High overall SVR12 rates (≥97%) after 8 and 12 weeks G/P

A useful resource

http://www.hep-druginteractions.org/

(or just google Hep C drug interactions)

SOF/LDV(Harvoni)

SOF/VEL(Epclusa)

GLE/PIB(Maviret)

GZV/EBV(Zepatier)

Pill Burden 1 daily 1 daily 3 am 1 pm 1 tab daily

Duration Naive

Experienced8-12 weeks12-24 weeks

12 weeks12 weeks

8-12 weeks8-12 weeks

12 weeks12-16 weeks

CirrhosisCompensated

DecompensatedSafeAdd RBV

SafeAdd RBV

SafeCannot use

SafeCannot use

Drug Interactions PPIAmio

PPIAmio

Some – look up

Resistance test Experienced None None All 1a

Need for RBV Decomp Decomp None 1a with resistance

SOF-Based Protease-Based When would I choose 1 over the

other?• SOF/LDV (Harvoni)

– G1a especially if HCV RNA<6 M IU/mL (8 weeks)

– Decompensated cirrhosis (with RBV)

• SOF/VEL (Epclusa)– Can’t think of any…maybe LDV resistance?

• EBV/GZV (Zepatier)– G1b

– Chronic kidney disease (eGFR<45 and for sure <30)

– Cannot stop PPI

• GLE/PIB (Maviret)– All non-cirrhotic patients can have 8 weeks of treatment,

even if high viral load

9/28/2018

5

A useful resource14- 02- 10 6:34 PMRecommendations for Testing, Managing, and Treating Hepatit is C

Page 1 of 3http:/ / www.hcvguidelines.org/

Recommendations for

Testing, Managing, and

Treating Hepatitis C

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 peer-

reviewed 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

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 PressRelease

Wednesday, January 29,

2014

View Official Press Release:

Online...

Read more >>

Home Full Report Panel Organizations Process Contact Us

Search website

www.hcvguidelines.org

But be careful – labels sometimes different in Canada vs US/Europe

Summary

• Rules for access – significantly improved

• Great options for genotype 1– Sofosbuvir + NS5A inhibitor (ledipasvir/velpatasvir)

– Grazoprevir/Elbasvir

– Glecaprevir/Pibrentasvir

• All highly effective and very safe – sometimes a ‘preferred choice’ but rarely a ‘wrong choice’

• Use the guidelines to make sure appropriate duration

• Look up drug interactions

Case – Rapid Fire

• 56M HCV G1b, VL 2.34x10E5 IU/mL

• Treatment Experienced

• F2

• Renal failure (GFR 22mL/min)

Options

• Preferred:

– EBV/GZP x 12 weeks

– GLE/PIB x 12 weeks (?unfunded)

• Less desirable:

– SOF/LDV x 8 weeks

– SOF/VEL x 12 weeks

GZP/EBV Renal Disease – C-SURFER

• 75% Dialysis• 45% Black• 52% G1a

Roth EASL 2015

• 83% Trt naive• 6% cirrhosis

Results

100

80

60

40

20

0

SV

R12 (

%)

94

115/122

Highly effective therapy in CKD

Kwo EASL 2015

• 2 LTFU• 1 non-compliance• 1 death (unrelated)• 1 w/d by subject• 1 w/d by MD

1 virological failure • G1b with NS5A RAV at

BL• Relapsed with NS5A and

PI RAVs

9/28/2018

6

Safety

Roth EASL 2015

SVR in CKD with SOF-based

therapy

eGFR<30

8/

10

1/

1

4/

4

100100 100100

80

60

40

20

0

SV

R1

2

(%)

n/N =

No obvious effect of GFR on response

2/

2

80

PR/

SOF

SOF/R SOF/

SIM SOF/

SIM/R

20/

25

1/

3

8/

10

30

80

100

9/

9

80

PR/

SOF

SOF/RSOF/

SIM

SOF/

SIM/R

eGFR 30-45

61/

68

37/

45

9384

92

12/

13

91

PR/

SOF

SOF/RSOF/

SIM

SOF/

SIM/R

13/

14

61/

55

2

37/

40

0

8172

79

12/

17

1

87

PR/

SOF

SOF/R

SOF/

SIM

SOF/

SIM/R

13/

23

2

eGFR 45-60 eGFR >60

Saxena EASL 2015

What about safety?Dichotomous = no (%)Continuous = mean (range)

eGFR ≤ 30

(N=17)

eGFR 30-45

(N=56)

eGFR 46-60

(N=157)

eGFR>60

(N=1,559) p-value

Common SOF AEs

Fatigue

Headache

Nausea

3 (18)

1 (6)

3 (18)

19 (34)

9 (16)

8 (14)

56 (36)

19 (12)

33 (21)

543 (35)

274 (18)

247 (16)

0.54

0.24

0.39

Anemia AE

Required Transfusion(s)Received Erythropoietin

6 (35)

2 (12)0 (0)

16 (29)

5 (9)6 (11)

37 (24)

3 (2)13 (8)

246 (16)

31 (2)46 (3)

<0.01

<0.01<0.01

RBV

Dose reduction for anemia

RBV Discontinuation3 (43)

0 (0)8 (30)4 (15)

33 (42)

1 (1)185 (19)

12 (1)<0.01

<0.01

Worsening Renal Function 5 (29) 6 (11) 4 (3) 14 (1) <0.01

Renal or Urinary System AEs 5 (29) 6 (11) 13 (8) 84 (5) <0.01

Serious AEs 3 (18) 13 (23) 8 (5) 100 (6) <0.01

Early Treatment Discontinuation 1 (5) 4 (6) 6 (4) 68 (4) 0.60

Early Treatment DC due to AE 1 (5) 2 (3) 4 (2) 39 (3) 0.53

Death 1 (5) 0 (0) 2 (1) 10 (1) 0.11

Saxena EASL 2015

But other small studies suggest less of a problem…SOF can be used in CKD carefully (but not the best for G1)

Thank You