Post on 18-Dec-2021
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