C型肝炎口服抗病毒藥(DAA)的藥物交互作用 台灣用藥分析

Chen-Hua Liu, MD, PhD

Hepatitis Research Center, and Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

Outline

• Novel therapeutic agents for HCV: IFN-free DAAs

- Concept

- Classes of IFN-free DAAs

- Efficacy of DAAs

- Points of the considered before using DAAs

• Drug-drug interactions (DDIs) between DAAs and concomitant medications

- Concept

- Overview of DDIs

- Real-world DDIs between DAAs and concomitant medications

Outline

• Novel therapeutic agents for HCV: IFN-free DAAs

- Concept

- Classes of IFN-free DAAs

- Efficacy of DAAs

- Points of the considered before using DAAs

• Drug-drug interactions (DDIs) between DAAs and concomitant medications

- Concept

- Overview of DDIs

- Real-world DDIs between DAAs and concomitant medications

• Potent

• Pan-genotypic

• Safe and well tolerated

• Easy dosing, simpler regimen, short duration

• No drug-drug interactions

• Inexpensive

The Ideal HCV Agents (Are We Getting Closer?)

Milestones of Antiviral Therapy for Hepatitis C Virus Infection

6

16

33

46 40

59

72

84

95

0

10

20

30

40

50

60

70

80

90

100

IFN 6m IFN 12m IFN/RBV 6m IFN/RBV12m

Peg-IFN 6m Peg-IFN/RBV12m

1st GenPI/PR

New DAA/PR IFN-freeDAAs

SVR

12 o

r SV

R24

(%

)

Response-guided therapy (RGT): 2004 IL28B genotypes: 2009 Direct-acting antiviral agents (DAAs): 2011 Pangenotypic IFN-free DAAs: 2016

1992-2000 2001-2010 2011-2013 ~ 2013

Potent Viral Suppression of DAAs Supersedes the Role of Other Factors in Determining the Therapeutic Outcomes

Antiviral effects

Immunology Host

activation pathways

Toxicity

Interferon-Based Therapy

Antiviral effects

DAA Interferon-Free Therapy

Others

• Cirrhosis • Viral genotypes • HIV co-infection • Host genetics

• Insulin resistance • Renal failure • Co-morbidities

Core E1 E2 P

7 NS2 NS3 NS4A NS4B NS5A NS5B

Therapeutic Targets for HCV (Licensed and Investigational)

5– –3

Telaprevir (Incivek) Boceprevir (Victrelis) RG7227 (Danoprevir) TMC435 (Simeprevir) MK-7009 (Vaniprevir) MK-5172 (Grazoprevir) BI201335 (Faldaprevir) BMS-650032 (Asunaprevir) ABT-450/r (Paritaprevir) ABT-493 (Glecaprevir)

GS-9857 (Voxilaprevir)

BMS790052 (Daclatasvir) GS-5885 (Ledipasvir) ABT-267 (Ombitasvir) MK-8742 (Elbasvir) GS-5816 (Velpatasvir) ABT-530 (Pibrentasvir) MK-8408 (Ruzasvir) PPI461 PPI668

Active site (nucleosides)

RG-7128 (Mericitabine) GS-7977 (Sofosbuvir) MK-3682 IDX184

Non-nucleosides

GS-9190 (Tegobuvir) BI207127 (Deleobuvir) TMC647055 Filibuvir (PF-00868554) VX-222 GS-9669 BMS791325 (Beclabuvir) ANA598 (Setrobuvir) ABT-072 ABT-333 (Dasabuvir)

NNI-site 1 NNI-site 1 NNI-site 1 NNI-site 2 NNI-site 2 NNI-site 2 NNI-site 1 & 2 NNI-site 3 NNI-site 3 NNI-site 4

NA3/4A Protease inhibitors NS5B Polymerase inhibitors

Host-targeted Antivirals

Debio025 (Alisporivir) SCY-635 Miravirsen (SPC3649) ITX-5061 ANA773 (TLR-7)

NS5A inhibitors

NS4B inhibitors

Clemizole

Currently Available IFN-free DAA Regimens in Taiwan (2017)

Characteristics DCV/ASV PrOD EBR/GZR SOF-Based

SOF/RBV LDV/SOF DCV/SOF

DAA class NS3

NS5A

NS3 NS5A

NS5B non-NUC

NS3 NS5A

NS5B NUC NS5A

NS5B NUC NS5A

NS5B NUC

Genotype coverage 1b 1, 4 1, 4 2, 3 1, 4, 5, 6 1-6

Treatment duration (wk) 24 12-24 12-16 12-16 12-24 12-24

Daily pills 3 4 1 1 1 2

Ribavirin - 1a 1a (RAS)

1a/1b (PI failure) 4 (prior on-Tx failure)

+ 1 (TE, cirrhosis)

1/4 (Child B/C, post-LTx)

3 (cirrhosis) Post-LTx

NS5A RAS test + (1b) - + (1a) - - -

Child B/C - - - + + +

CKD 4/5 + + + - - -

DDI ++ +++ + + + +

FDA/EMA approval - + + + + +

Reimbursement (Taiwan) + + - - - -

DAA: direct acting antiviral agent, DCV: daclatasvir, ASV: asunaprevir, PrOD: paritaprevir/ritonavir/ombitasvir/dasabuvir, EBR: elbasvir, GZR: grazoprevir, SOF: sofosbuvir, RBV: ribavirin, LDV: ledipasvir, NS: non-structural, NUC: nucleoside analogue, wk: week, RAS: resistance associated substitution, CKD: chronic kidney disease, DDI: drug-drug interaction

Daclatasvir/Asunaprevir for HCV-1b Patients (with/without NS5A RAVs)

90 82 82

0

20

40

60

80

100

Naïve Nonresponse Ineligible/intolerant

HALLMARK-DUAL Treatment-naïve/experienced

Non-cirrhotic/cirrhotic

182/203 168/205 192/235

Manns M, et al. Lancet 2014;384:1597-605

McPhee F, et al. Adv Ther 2015;32:637-49

39

94

0

20

40

60

80

100

L31 or Y93 RAV (+) L31 or Y93 RAV (-)

55/141 787/838

SVR

12 (

%)

SVR

12 (

%)

* NS5A RAV evaluated by population sequencing with a cutoff value of 15-20%

HALLMARK-DUAL

• Phase 3 study

• HCV-1b patients (treatment-naïve, prior non-

responders, relapsers)

• Treatment: daclatasvir/asunaprevir (DCV/ASV) for

24 weeks

• Fibrosis: F0-4, Child A cirrhosis

99

0

20

40

60

80

100

LDV/SOF 12 Wk

Ledipasvir/Sofosbuvir ± RBV for HCV-1 Patients

ION-I Treatment-naïve

Non-cirrhotic/cirrhotic

ION-II Treatment-experience Non-cirrhotic/cirrhotic

SVR

12 (%

)

94 96

0

20

40

60

80

100

LDV/SOF 12 Wk LDV/SOF/RBV 12 Wk

90 96

0

20

40

60

80

100

LDV/SOF 12 Wk LDV/SOF/RBV 12 Wk

Reddy Treatment-experience

cirrhotic

211/214 102/109 107/111

64/71 152/159

Afdhal N, et al. N Engl J Med 2014;370:1889-98

Afdhal N, et al. N Engl J Med 2014;370:1483-93

SIRIUS PI Treatment-experience

cirrhotic

96 97

0

20

40

60

80

100

LDV/SOF/RBV 12 Wk LDV/SOF 24 Wk

SVR

12 (

%)

74/77 75/77

Reddy KR, et al. Hepatology 2015;62:79-86

Bourlière M, et al. Lancet Infect Dis 2015;15:397-404

ION I & II

• Phase 3 study

• HCV-1 patients (treatment-naïve

or experienced)

• Treatment: ledipasvir/sofosbuvir

± RBV for 12-24 weeks

• Fibrosis: F0-4, Child A cirrhosis

Ledipasvir/Sofosbuvir ± RBV for Treatment-Naive HCV-1 Non-Cirrhotic Patients (High or Low Viral Load)

Kowdley KV, et al. N Engl J Med 2014;370:1879-88

94 95

0

20

40

60

80

100

LDV/SOF 8 Wk LDV/SOF 12 Wk

ION-III Treatment-naive

Non-cirrhotic

202/215 206/216

97 96

0

20

40

60

80

100

LDV/SOF 8 Wk LDV/SOF 12 Wk

SVR

12 (

%)

ION-III Treatment-naive

Non-cirrhotic (VL < 6 M/mL)

ION-III Treatment-naive

Non-cirrhotic (VL ≥ 6 M/mL)

90 94

0

20

40

60

80

100

LDV/SOF 8 Wk LDV/SOF 12 Wk

ION III

• Phase 3 study

• Treatment-naïve HCV-1 patients

• F0-F3

• Treatment: ledipasvir/sofosbuvir for 8 weeks

Ombitasvir/Paritaprevir/Ritonavir plus Dasabuvir + RBV for HCV-1a Patients

SAPPHIRE-I Treatment-naïve

Non-cirrhotic

95.3

0

20

40

60

80

100

PrOD/RBV 12 Wk

SVR

12 (

%)

307/322

SAPPHIRE-II Treatment-experienced

Non-cirrhotic

96.0

0

20

40

60

80

100

PrOD/RBV 12 Wk

166/173

88.6 94.2

0

20

40

60

80

100

PrOD/RBV 12 Wk PROD/RBV 24 Wk

SVR

12 (

%)

TORQUOISE-II Treatment-naïve/experienced

Cirrhotic

124/140 114/121

Poordad F, et al. N Engl J Med 2014;370:1973-82

Feld J, et al. N Engl J Med, 2014;370:1594-603

Zeuzem S, et al. N Engl J Med, 2014;370:1604-14

SAPPHIRE-I & II

• Phase 3 study

• HCV-1a patients (treatment-

naïve or experienced)

• Treatment: PrOD + RBV for 12

weeks

• Fibrosis: F0-3

TURQUOISE-II

• Phase 3 study

• HCV-1 patients (treatment-naïve

and experienced)

• Treatment: PrOD + RBV for 12 or

24 weeks

• Fibrosis: F4, Child A

Ombitasvir/Paritaprevir/Ritonavir plus Dasabuvir ± RBV for HCV-1b Non-Cirrhotic Patients

SAPPHIRE-I Treatment-naïve

Non-cirrhotic

98.0

0

20

40

60

80

100

PrOD/RBV 12 Wk

SVR

12 (

%)

148/151

SAPPHIRE-II Treatment-experienced

Non-cirrhotic

96.7

0

20

40

60

80

100

PrOD/RBV 12 Wk

119/123

99.5 99.0

0

20

40

60

80

100

PrOD/RBV 12 Wk PrOD 12 Wk

PEARL-III Treatment-naïve

Non-cirrhotic

209/210 207/209

96.6 100.0

0

20

40

60

80

100

PrOD/RBV 12 Wk PrOD 12 Wk

SVR

12 (

%)

PEARL-II Treatment-experienced

Non-cirrhotic

Ferenci P, et al. N Engl J Med 2014;370:1983-92

Andreone P, et al. Gastroenterology 2014;147:359-65

85/88 91/91

Feld J, et al. N Engl J Med, 2014;370:1594-603

Zeuzem S, et al. N Engl J Med, 2014;370:1604-14

SAPPHIRE-I & II

• Phase 3 study

• HCV-1b patients (treatment-

naïve or experienced)

• Treatment: PrOD + RBV for 12

weeks

• Fibrosis: F0-3

PEARL-II & III

• Phase 3 study

• HCV-1b patients (treatment-

naïve or experienced)

• Treatment: PrOD ± RBV for 12

weeks

• Fibrosis: F0-3

Ombitasvir/Paritaprevir/Ritonavir plus Dasabuvir ± RBV for HCV-1b Cirrhotic Patients

TORQUOISE-II Treatment-naïve/experienced

Cirrhotic

98.5 100.0

0

20

40

60

80

100

PrOD/RBV 12 Wk PrOD/RBV 24 Wk

SVR

12 (

%)

TORQUOISE-III Treatment-naïve/experienced

Cirrhotic

67/68 51/51

100.0

0

20

40

60

80

100

PrOD 12 Wk

60/60

Poordad F, et al. N Engl J Med 2014;370:1973-82

Feld JJ, et al. J Hepatol 2016;64:301-7

SVR

12 (

%)

TURQUOISE-II

• Phase 3 study

• HCV-1 patients (treatment-naïve

and experienced)

• Treatment: PrOD + RBV for 12

weeks

• Fibrosis: F4, Child A

TURQUOISE-III

• Phase 3 study

• HCV-1 patients (treatment-naïve

and experienced)

• Treatment: PrOD for 12 weeks

• Fibrosis: F4, Child A

Grazoprevir/Elbasvir ± Ribavirin for HCV-1 Patients (with/ without NS5A RAVs)

C-EDGE TN/TE 1a Treatment-naïve/experienced

No NS5A RAV

C-EDGE TN/TE 1a Treatment-naïve/experienced

NS5A RAV

98

0

20

40

60

80

100

GZR/EBR 12 Wk

441/450 6/6

70

100

0

20

40

60

80

100

GZR/EBR 12 Wk GZR/EBR/RBV 16 Wk

39/56 6/6

C-EDGE TN/TE 1b Treatment-naïve/experienced

No NS5A RAV

94

0

20

40

60

80

100

GZR/EBR 12 Wk

C-EDGE TN/TE 1b Treatment-naïve/experienced

NS5A RAV

99

0

20

40

60

80

100

GZR/EBR 12 Wk

48/51 247/248

Zeuzem S, et al. Ann Intern Med 2015;163:1-13

Kwo P, et al. Gastroenterology 2017;152:164-75

SVR

12 (

%)

SVR

12

(%)

C-EDGE TN/TE-1a

• Phase 3 study

• HCV-1a patients (treatment-

naïve and experienced)

• Treatment: GZR/EBR ± RBV for

12 or 16 weeks

• Fibrosis: F0-F4, Child A

C-EDGE TN/TE-1b

• Phase 3 study

• HCV-1b patients (treatment-

naïve and experienced)

• Treatment: GZR/EBR ± RBV for

12 weeks

• Fibrosis: F0-F4, Child A

Sofosbuvir/Ribavirin for HCV-2 Patients FISSION

Treatment-naïve

97 98 91

0

20

40

60

80

100

SOF/RBV12 Wk No cirrhosis Cirrhosis

68/70 58/59 10/11

SVR

12 (

%)

86 96

60 78

0

20

40

60

80

100

SOF/RBV12 Wk No cirrhosis Cirrhosis (12 Wk)Cirrhosis (16 Wk)

FUSION Treatment-experienced

31/36 25/26 6/10 7/9

POSITRON Ineligible, intolerant, unwilling

93 92 94

0

20

40

60

80

100

SOF/RBV12 Wk No cirrhosis Cirrhosis

101/109 85/92 16/17

SVR

12 (

%)

VALENCE Treatment-naïve/experienced

Lawitz E, et al. N Engl J Med 2013;368:1878-87

Jacobson IM, et al. N Engl J Med 2013;368:1867-77

Zeuzem S, et al. N Engl J Med 2014;370:1993-2001

93 97 91 100 78

0

20

40

60

80

100

SOF/RBV12 Wk TN, LC (-) TE, LC (-) TN, LC (+) TE, LC (+)

68/73 29/30 30/33 2/2 7/9

Factors Should Be Considered Before Choosing an Optimized Treatment Regimen for HCV

Category Factors

Viral

• HCV genotype/subtype

• Viral load

• Resistance (RAS)

Treatment

• HCV treatment history

– PR

– PI-based triple therapy

– Sofosbuvir plus PR

– IFN-free DAAs

• RBV eligibility

Fibrosis stage

• Cirrhosis of not ?

• If cirrhotics, how about Child-Pugh score ?

• If cirrhotic, any history of decompensation ?

• Transplant evaluation if necessary

Coinfection/comorbidities

• HBV, HIV co-infection

• Cardiovascular, renal, metabolic, cancer, and other concerns

• Drug–drug interactions (DDI)

Financial • Insurance reimbursement (NHI)

Outline

• Novel therapeutic agents for HCV: IFN-free DAAs

- Concept

- Classes of IFN-free DAAs

- Efficacy of DAAs

- Points of the considered before using DAAs

• Drug-drug interactions (DDIs) between DAAs and concomitant medications

- Concept

- Overview of DDIs

- Real-world DDIs between DAAs and concomitant medications

Potential Interactions of DAAs for HCV and Concomitant Medications

Direct Acting Antiviral Agents

(DAA)

Concomitant Medications for Comorbidities

Mechanism Effects Effects

Enzyme induction DAA-induced

↓ Drug level

Enzyme inhibition ↑ Drug level

Enzyme induction ↓ Drug level Co-medication-induced

Enzyme inhibition ↑ Drug level

Substrate ↑ Drug level ↑ Drug level

Characteristics of Direct-Acting Antiviral Drugs

Drug Inhibition Induction Substrate

Asunaprevir Moderate inhibitor of CYP2D6 Weak inhibitor of CYP3A4

and P-gp

Substrate of CYP3A4, P-gp

and OATP1B1

Daclatasvir Moderate inhibitor of P-gp and

OATP

NA Substrate of CYP3A and P-gp

Ledipasvir Mild inhibitor of P-gp, BCRP NA Substrate of P-gp

Sofosbuvir NA NA Substrate of P-gp

Simeprevir Mild inhibitor of intestinal CYP3A

and CYP1A2; mild inhibitor of OATP

and P-gp

NA Substrate of CYP3A

Paritaprevir/ritonavir,

ombitasvir, dasabuvir

Inhibitor of CYP3A4, CYP2D6, P-gp,

OATP, and BCRP

Inhibitor of CYP1A2,

CYP2C8, CYP2C9, and

CYP2C19 (based on

ritonavir PKs)

Substrate of CYP3A4,

CYP2C8, and CYP2D6

Lucas Hill., HCV DAA Drug Interactions Volume 23 Issue 2

Drug-Drug Interaction (I)

Class Drug DCV ASV PrOD SMV GZR/EBR SOF LDV/SOF VEL/SOF

Antiarrythmics

Amiodarone

Dronedarone

Digoxin

Disopyramide

Quinidine

Flecainide

Propafenone

Vernakalant

Antiplatelet and anticoagulant

Clopidogrel

Ticagrelor

Dabigatran

Rivaroxaban

Eltrombopag

Warfarin

Heparin

No clinically significant interaction expected Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring Should not be co-administered

Drug-Drug Interaction (II)

Class Drug DCV ASV PrOD SMV EBR/GZR SOF LDV/SOF VEL/SOF

𝜶-blocker

Doxazocin

Alfuzocin

Tamsulosin

𝜷-blocker

Atenolol

Bisoprolol

Carvedilol

Metoprolol

Propranolol

Calclium channel blocker

Amlodipine

Felodipine

Nifedipine

Lercanidipine

Diltiazem

Angiotensin converting enzyme inhibitor

Benazepril

Captopril

Enalapril

Angiotensin receptor blocker

Azilsartan

Candesartan

Irbesartan

Losartan

Olmesartan

Telmisartan

Valsartan

No clinically significant interaction expected Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring Should not be co-administered

Drug-Drug Interaction (III)

Class Drug DCV ASV PrOD SMV EBR/GZR SOF LDV/SOF VEL/SOF

Diuretics

Amiloride

Furosemide

Bumetanide

Indapamide

Spironolactone

Hydralazine

Hydrocholrothiazide

Fibrate

Bezafibrate

Fenofibrate

Gemfibrozil

Cholesterol absorption inhibitor

Ezetimibe

HMG-CoA reductase inhibitor

Atorvastatin

Fluvastatin

Lovastatin

Pitavastatin

Pravastatin

Rosuvastatin

Simvastatin

No clinically significant interaction expected Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring Should not be co-administered

Drug-Drug Interaction (IV)

Class Drug DCV ASV PrOD SMV EBR/GZR SOF LDV/SOF VEL/SOF

𝜶-glucosidase inhibitor

Acarbose

Biguanide Metformin

DPP-4 inhibitor

Linagliptin

Vildagliptin

Saxagliptin

Sitagliptin

GLP-1 agonist Liraglutide

Meglitinide Repaglinide

SGLT-2 inhibitor Dapaglifozin

Empaglifozin

Thiazolidinedione Pioglitazone

Rosiglitazone

Sulfonylurea

Gliclazide

Glimepiride

Glipizide

Glyburide

Insulin Insulin

No clinically significant interaction expected Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring Should not be co-administered

Drug-Drug Interaction (V) Class Drug DCV ASV PrOD SMV EBR/GZR SOF LDV/SOF VEL/SOF

HBV agents

Lamivudine

Adefovir

Entecavir

Telbivudine

Tenofovir

HCV agent

Ribavirin

Sofosbuvir

Peginterferon

Ledipasvir/sofosbuvir

HIV NRTI

Abacavir

Didanosine

Stavudine

Zidovudine

Tenofovir/ Emtricitabine

HIV NNRTI

Efavirenz

Nevirapine

Etravirine

Rilpivirine

HIV PI

Atazanavir

Darunavir

Lopinavir

Ritonavir

Integrase inhibitor

Dolutegravir

Raltegravir

No clinically significant interaction expected Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring Should not be co-administered

Drug-Drug Interaction (VI) Class Drug DCV ASV PrOD SMV EBR/GZR SOF LDV/SOF VEL/SOF

Opioid analgesics Morphine

Tramadol

NSAID / aspirin acetaminophen

Aspirin

Acetaminophen

Diclofenac

Ibuprofen

Indomethacin

Ketoprofen

Naproxen

Piroxicam

COX-2 inhibitor

Celecoxib

Etoricoxib

Meloxicam

TB drugs

Ethambutol

Rifabutin

Rifampicin

Isoniazid

Pyrazinamide

Macrolides

Erythromycin

Clindamycin

Clarithromycin

Quinolone Ciprofloxacin

Levofloxacin

Cephalosporin Cefalexin

Cefaclor

Drug-Drug Interaction (VII) Class Drug DCV ASV PrOD SMV EBR/GZR SOF LDV/SOF VEL/SOF

Antifungal

Fluconazole

Itraconazole

Ketoconazole

Voriconazole

Miconazole

Antihistamine

Diphenhydramine

Cetirizine

Fexofenadine

Levocetirizine

Loratadine

Immunosuppressant

Cyclosporine

Tacrolimus

Sirolimus

Everolimus

Azathioprine

Mycophenolate mofetil

Steroid

Betamethasone

Dexamethasone

Budesonide

Hydrocortisone

Methylprednisolone

Others

Allopurinol

Dextromethorphan

Levothyroxine

Ursodeoxycholic acid

No clinically significant interaction expected Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring Should not be co-administered

Drug-Drug Interaction (VIII) Class Drug DCV ASV PrOD SMV EBR/GZR SOF LDV/SOF VEL/SOF

Others

Baclofen

Estradiol

Ethinylestradiol

Pentoxifylline

Sorafenib

Thalidomide

Tamoxifen

Anxiolytics

Alprazolam

Diazepam

Estazolam

Lorazepam

Midazolam

Zolpidem

Zopiclone

Antidepressant

Amitriptyline

Escitalopram

Imipramine

Sertraline

Antipsychosis Thioridazine

Antiepileptics

Carbamazepine

Clonazepam

Gabapentin

Phenobarbital

Phenytoin

Valproate

No clinically significant interaction expected Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring Should not be co-administered

High Prevalence of Co-Morbidities and Complex Polypharmacy with DDI in Patients with CHC

• Objectives: To describe the prevalence of comorbidities and co-medications with DDI potential with the 4 currently licensed DAAs in large sample of CHC patients in primary care in UK, Germany and France (n = 7,946)

Marra F, et al. AASLD 66th Annual Meeting, San Francisco, CA, 2015

Most Frequent Comorbidities by Country

UK (n = 4,644) Germany (n = 2,735) France (n = 567)

Comorbidity-Read Prevalence Comorbidity- ICD10 Prevalence Comorbidity- ICD10 Prevalence

1 Depression 23.2% Chronic pain syndrome (R52.1, R52.2), M54 (back pain)

22.7% Chronic pain syndrome (R52.1, R52.2), M54 (back pain)

15.7%

2 CVD 21.0% Hypertension (I10) 22.1% Hypertension (I10) 15.7%

3 COPD/Asthma 14.4% Depression (F32, F33) 14.7% Diabetes Type 2 (E11, E14) 8.6%

4 Pain 7.7% Chronic gastritis (K29) 10.7% Anxiety/Pain disorder (F41) 8.1%

5 Substance use 4.1% GORD (K20-23) 10.2% Depression (F32, F33) 6.5%

6 GORD 3.4% Polytoxicomania (F19) 9.2% Polytoxicomania (F19) 5.1%

7 Diabetes 3.1% Diabetes Type 2 (E11) 8.3% GORD (K20-23) 4.2%

8 Psychosis/ Schizophrenia

3.0% Dyslipidemia (E78) 6.6% Asthma bronchiale (J56, J46) 3.3%

9 Epilepsy 2.3% COPD (J44) 6.2% Chronic gastritis (K29) 2.8%

10 Chronic gastritis 2.2% Alcohol abuse (F10.2) 5.5% COPD (J44) 2.6%

High Prevalence of Co-Morbidities and Complex Polypharmacy with DDI in Patients with CHC

Prevalence of Top 5 RED and Top 10 AMBER Prescriptions to ≥ 1 DAA, by Country

UK (n = 4,644) Germany (n = 2,735) France (n = 567)

Substance % of Patients Substance % of Patients Substance % of Patients

RED

≥ 1

1 Clarithromycin 5.3% Bisoprolol 6.6% Domperidone 6.7%

2 Simvastatin 4.8% Simvastatin 4.6% Atorvastatin 3.0%

3 Salmeterol 4.4% Quetiapine 1.6% Bisoprolol 2.6%

4 Atorvastatin 3.1% Clarithromycin 1.3% Clarithromycin 2.5%

5 Quetiapine 3.0% Domperidone 1.2% Lercanidipine 2.3%

AM

BER

≥ 1

1 Omeprazole 19.6% Pantoprazole 21.9% Esomeprazole 13.9%

2 Codeine 15.4% Levothyroxine Sodium 9.3% Omeprazole 9.9%

3 Diazepam 13.4% Omeprazole 8.6% Zolpidem 9.2%

4 Mirtazapine 11.6% Amlodipine 5.4% Zopiclone 7.4%

5 Zopiclone 10.2% Doxepin 4.7% Oxazepam 7.1%

6 Lansoprazole 8.1% Formoterol 4.6% Pantoprazole 6.7%

7 Tramadol 7.5% Mirtazapine 4.1% Levothyroxine Sodium 6.7%

8 Prednisolone 7.1% Prednisolone 3.5% - Alprazolam 6.0%

9 Sertraline 6.6% Furosemide 3.5% - Furosemide - Tramadol & combinations

5.8%

10 Amlodipine 5.2% Tramadol 3.1% - Prednisolone - Codeine combination

5.5%

Marra F, et al. AASLD 66th Annual Meeting, San Francisco, CA, 2015

Drug-Drug Interactions with Novel All Oral IFN-Free DAAs in a Large Real-World Cohort

• Design: 261 HCV-monoinfected patients receiving DAA between 2011 and 2014; potential DDI for SOF/RBV, LDV/SOF, SOF/DCV, SOF/SIM, PrO ± D, TVR, and BOC

Höner Zu Siederdissen C, et al. Clin Infect Dis 2016;62:561-7

20 18

12

16

10 7 7

5 2 2 2

0

5

10

15

20

25

30

0 1 2 3 4 5 6 7 8 9 ≥ 10

Number of drugs

Pro

po

rtio

n o

f th

e st

ud

y co

ho

rt (

%)

46%

24% 9%

Drug Class 3rd Level Anatomical Therapeutic Chemical Classification System Code

Affected Patients (n)

Affected Portion of the Study Cohort (%)

PPI A02BC 63 24.1

Selective β blockers C07AB 48 18.4

Aldosterone antagonist C03DA 44 16.9

Thyroid hormone H03AA 43 16.5

ARB C09CA 34 13.0

ACEI C09AA 29 11.1

Dihydropyridine Ca++ blockers C08CA 28 10.7

Thiazide C03AA 26 10.0

Sulfonamide C03CA 24 9.2

Non-selective β blockers C07AA 21 8.0

Drug-Drug Interactions with Novel All Oral IFN-Free DAAs in a Large Real-World Cohort

Höner Zu Siederdissen C, et al. Clin Infect Dis 2016;62:561-7

9.6

31.0 36.4

40.2

57.9 57.9

44.8 49.0

0.0

0.4

0.4 0.0

8.4 8.4

8.8 6.1

0

10

20

30

40

50

60

70

SOF/RBV SOF/SMV SOF/DCV SOF/LDV 3D 2D TVR/PR BOC/PR

Monitor/may require dose adjustment (Category 2) Contraindication (Category 3)

Pro

po

rtio

n o

f p

atie

nts

w

ith

sig

nif

ica

nt

DD

I (%

)

Co-medication and Potential Drug to Drug Interactions in CHC: Implications for Adequate HCV Treatment Selection

< 18 yrsn = 4

18-29 yrsn = 118

30-39 yrsn = 513

40-49 yrsn = 898

50-59 yrsn = 1,011

60-69 yrsn = 541

≥ 70 yrs n = 525

GZR/EBR 0 1 7 33 36 30 33

DCV/SOF 0 0 5 20 22 20 21

SMV/SOF 0 3 19 57 62 34 26

PrOD 1 11 43 106 155 110 129

LDV/SOF 0 0 4 23 30 17 6

0

100

200

300

400

Patients with potential CI co-medication per DAA

• Design: cross-sectional study from general practice and gastroenterologists in Germany and France between 01/2012 and 12/2015. Co-medications with DDI potential for DAAs were obtained from an established DDI database www.hep-druginteractions.org/

• Patients (n = 3610): 84% and 16% from Germany and France respectively. 42% were females; mean age was 52.4 and 57.3 years for German and French cohorts respectively. 29.5% were ≥ 60 years old.

DAA Potential CI (%)

LDV/SOF 2.2

DCV/SOF 2.4

GZR/EBR 3.9

SMV/SOF 5.6

PrOD 15.5

Results suggest frequent use of CI co-medications with DDI potential among real world CHC patients. Prevalence of CI co-medication increases with age and varies by DAA.

Christensen S, et al. AASLD 67th Annual Meeting, Boston, MA, 2016

Efficacy and Safety of DAA and Clinical Significance DDIs for Elderly Patients with Chronic HCV Infection

• Design: real-world cohort of efficacy, safety and DDI in HCV patients ≥ 65 years (n = 137) or < 645 years (n = 404) receiving SOF-based or PrOD (PrO)-based DAAs with and without RBV for HCV GT 1-4 in German

Vermehren J, et al. Aliment Pharmacol Ther 2016;44:856-65

< 65 y (n = 404) ≥ 65 y (n = 137) 65-74 y (n = 96) ≥ 75 y (n = 41)

Age, y, mean (range) 51 (18, 64) 72 (65, 86) 69 (65, 74) 78 (75, 86)

Male, n (%) 252 (62) 64 (47) 46 (48) 18 (44)

HCV GT, n (%)

1a 124 (31) 36 (26) 26 (27) 10 (24)

1b 171 (42) 84 (61) 58 (61) 26 (64)

2/3 83 (21) 15 (11) 10 (10) 5 (12)

Other 26 (6) 2 (2) 2 (2) -

Cirrhosis, n (%) 157 (39) 64 (47) 40 (42) 24 (59)

TE, n (%) 229 (57) 76 (55) 55 (57) 21 (51)

HCV RNA, log10 IU/mL, mean (SD) 6.0 (0.8) 6.1 (0.6) 6.1 (0.7) 6.1 (0.5)

eGFR, mL/min, mean (SD) 97.5 (16.7) 76.5 (17.4) 78.9 (17.3) 70.3 (16.5)

Hb, g/dL, mean (SD)

Female 14.8 (1.8) 13.4 (1.6) 13.9 (1.9) 13.1 (1.8)

Male 13.7 (1.3) 14 (1.9) 13.5 (1.4) 14.2 (2.0)

Treatment regimen, n (%)

SOF/LDV ± RBV 185 (46) 68 (50) 48 (50) 20 (48)

SOF/DCV ± RBV 75 (19) 21 (15) 12 (13) 9 (22)

PTV/OBV ± DSV ± RBV 57 (14) 22 (15) 18 (19) 4 (10)

SOF/SMV ± RBV 46 (11) 13 (10) 9 (9) 4 (10)

SOF + RBV 40 (10) 13 (10) 9 (9) 4 (10)

Efficacy and Safety of DAA and Clinical Significance DDIs for Elderly Patients with Chronic HCV Infection

Vermehren J, et al. Aliment Pharmacol Ther 2016;44:856-65

95 98 90

96 87

100 100 100 100 100 100 100 100 100 100

0

20

40

60

80

100

All LDV/SOF ± RBV DCV/SOF ± RBV PTV/OBV ± DSV± RBV

SMV/SOF ± RBV

SVR12 (%) in HCV GT-1/4 < 65 y ≥ 65 y ≥75 yr

91 91 100

83 100 100 100 100

0

20

40

60

80

100

All DCV/SOF ± RBV LDV/SOF ± RBV SOF + RBV

SVR12 (%) in HCV GT-3 < 65 y ≥ 65 y ≥75 yr

295/311 119/119 35/35 168/172 71/71 21/21 36/40 15/15 7/7 53/55 20/20 3/3 38/44 13/13 4/4

49/54 3/3 1/1 29/32 3/3 1/1 10/10 ** 10/12 **

Only patients who completed ≥ 80% of the intended treatment duration and who had a known virologic outcome are included. ** No patients aged 65 years and older were treated with LDV/SOF and SOF + RBV

33 29 30 17 15

0

20

40

60

80

100

< 65 y

Predicted DDI (%) [grade 2/3] LDV/SOF ± RBVDCV/SOF ± RBVPTV/OBV ± DSV ± RBVSMV/SOF ± RBVSOF + RBV

56 75

61 44

22

020406080

100

65-74 y

55 44

100

25 15

020406080

100

≥ 75 y

• DDI: 54% vs. 28% (p < 0.0001) [≥ 65 y vs. < 65 y] • Concomitant medication: 79% vs. 51% (p < 0.0001) [≥ 65 y vs. < 65 y] • SVR: 98% vs. 91% [≥ 65 y vs. < 65 y]

• AE: 63% vs. 65% (p = n.s.) [≥ 65 y vs. < 65 y]

Co-morbidities, Concomitant Medications and Potential Drug-Drug Interactions in HCV Patients: INITIATE Study

Liu CH, et al. APASL 26th Annual Meeting, Shanghai, China, 2017

• Design: multicenter, prospective, cross-sectional, observational study, 822 CHC patients were recruited from 11 hospitals across Taiwan between 30th May 2016 – 26th August 2016

Co-morbidities • Co-morbidities were

categorised by the International Classification of Diseases-10th Revision (ICD-10).

DDIs • Traditional Chinese

Medicines, herbals, liver protectants and supplements were excluded from the DDI analysis.

• The main active ingredients of the remaining were checked for DDIs with CHC regimens using the University of Liverpool HEP Drug Interaction Checker and the prescribing information for asunaprevir.

Patient demographics Clinical characteristics Co-medications Physician

recommendation and patient willingness to receive PEG-IFN+RBV

Physician survey

Patient survey

Reasons for being unwilling to accept PEG-IFN+RBV

HCV patient

Active, CHC infection ≥20 years old

Inclusion criteria

Exclusion criteria

Acute HCV infection Receiving DAA or IFN-based therapy

Recommended but unwilling to accept

PEG-IFN+RBV

Co-morbidities, Concomitant Medications and Potential Drug-Drug Interactions in HCV Patients: INITIATE Study

Liu CH, et al. APASL 26th Annual Meeting, Shanghai, China, 2017

Characteristics All

(N = 822)

TN

(n = 490)

TE

(n = 322)

Age, mean (years) 62.7 (64.0) 62.6 (64.0) 62.9 (64.0)

Age group, n (%)

<50 years

50–64 years

≥65 years

108 (13.1)

308 (37.5)

406 (49.4)

76 (15.5)

172 (35.1)

242 (49.4)

32 (9.6)

136 (41.0)

164 (49.4)

Gender, n (% of male)

Male

334 (40.6)

196 (40.0)

138 (41.6)

HCV genotype, n (%)

1

2

Other

434 (52.8)

220 (26.8)

168 (20.4)

202 (41.2)

161 (32.9)

127 (25.9)

232 (69.8)

59 (17.7)

41 (12.3)

Cirrhosis status, n (%)

No cirrhosis

Compensated

cirrhosis

Decompensated

cirrhosis

Unknown

551 (67.0)

207 (25.2)

61 (7.4)

3 (0.4)

350 (71.4)

100 (20.4)

38 (7.8)

2 (0.4)

201 (60.5)

107 (32.2)

23 (6.9)

1 (0.3)

18.5%

27.1%

35.2%

38.7%

40.2%

0% 10% 20% 30% 40% 50%

Diseases of the genitourinary system(e.g. chronic kidney disease, benign

prostate hypertrophy)

Mental and behavioural disorders(e.g. depression, insomnia)

Endocrine, nutritional and metabolicdiseases

(e.g. diabetes mellitus, dyslipidemia)

Diseases of the circulatory system(e.g. hypertension, coronary heart

disease)

Diseases of the digestive system(e.g. gastritis, gastro esophagel reflux

disease)

The 5 most prevalent co-morbidities by ICD-10 category (n=822) [86.3% had at least one co-morbidity]

Age group ≥ 1 concomitant

medications (%)

Mean concomitant

medications (n)

All patients 75.9% 3.4

<50 years 61.1% 1.8

50-64 years 72.7% 3.1

≥65 years 82.3% 4.0

• 20.4% of patients were receiving TCMs, herbals, supplements or vitamins

• 35.8% of patients were receiving liver protectants • Most common concomitant medications: HTN/HF agents (28.0%),

GI agents (25.7%), psychiatric agents (21.5%)

Co-morbidities, Concomitant Medications and Potential Drug-Drug Interactions in HCV Patients: INITIATE Study

Liu CH, et al. APASL 26th Annual Meeting, Shanghai, China, 2017

39.3

18.5

38.8

15

36.6

25.8

35.5

24.1

32.1

40.9

33.5 44.6 31.8

41.6

20.4

1.5 1.3 5.4 11.3 2.1

0

20

40

60

80

100

SOF + RBV LDV/SOF DCV/ASV OBV/|PTV/r+DSV EBR/GZR

Potential DDIs in Patients with CHC

Information not available No potential DDI Monitoring required Contraindicated

0

20

40

60

80

100

Nu

mb

er

of

Co

ntr

ain

dic

ate

d D

DIs

Antimicrobials

Cardiovascular drugs

Central nervous system drugs

Gastrointestinal agents

HIV Drugs

Immunosuppressants

Lipid lowering agents

Other agents

0

150

300

450

600

750

900

Nu

mb

er

of

DD

Is c

lose

mo

nit

ori

ng

AntimicrobialsCardiovascular drugsCentral nervous system drugsGastrointestinal agentsHIV DrugsImmunosuppressantsLipid lowering agentsOther agents

Summary

• IFN-free DAAs are potent and generally safe to treat HCV patients

• Pre-treatment DDIs checks are important before choosing an optimized

treatment regimen

• The Liverpool web check is easy to use for the DDI checks

• Real-world data shows that SOF-based and EBR/GZR have fewer potential DDIs

than PrOD and DCV/ASV for HCV

Thank You for Your Attention