Current Status and Benefits of
Therapy for Chronic Hepatitis C
Virus (HCV)
Fuad AM Hasan
Department Of Medicine
Faculty of Medicine
Kuwait University
Current Status and Benefits of
Therapy for Chronic Hepatitis C
Virus (HCV)
Fuad AM Hasan
Department Of Medicine
Faculty of Medicine
Kuwait University
Current And Future Treatment of HCV:
The Count Down To The Demise of
Hepatology
Fuad AM Hasan
Department Of Medicine
Faculty of Medicine
Kuwait University
True or False
• Hepatitis C is incurable. Treatment only
suppresses the virus
• Interferon and ribavirin therapy are associated
with minor adverse events
• HCV genotype is a major determinant of response
to interferon based therapy.
• Boceprevir and telaprevir are effective against all
genotypes.
• Sofosbuvir in combination with IFN and ribavirin
cures around 90% of HCV infected patients
Outline
•
•
•
•
HCV structure and life cycle
HCV genotypes
Standard treatment of HCV (2001-2011)
Standard treatment of HCV genotype 1 (20112013)
• Current treatment of HCV genotypes 1-6
• The future
HCV Polyprotein Processing
and Viral Protein Function
McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48:1700-12
HCV Life Cycle and DAA Targets
NS5A inhibitors
Block replication complex formation, assembly
Receptor binding
and endocytosis
Transport
and release
Fusion and
uncoating
Translation and
polyprotein
processing
NS3/4
protease
inhibitors
ER lumen
(+) RNA
LD
LD
LD
Membranous
web
ER lumen
Virion
assembly
NS5B polymerase
inhibitors
RNA
replication
Nucleoside/nucleotide
RNA replication
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
Nonnucleoside
HCV Genotypes
The Prevalence of HCV Genotype 4 in Kuwait
100
80
>90
100*
71
62
Kuwait
Egyptian
Syrian
Saudi
60
40
20
0
Kuwait
* Eastern province of Syria
Egyptian
Syrian
Saudi
Hasan et al. Hepatogastroenterology 2002
Seroprevalence of HCV in Kuwait
20
18
16
14
12
10
8
6
4
2
0
kuwaiti blood Non Kuwaiti
donors
blood donors
T2 diadetes:
kuwaiti
T2 diadetes:
Egyptian
Civil service
applicants*
Ameen R et al. Transfusion. 2005 ;45:1973-80.
Chehada W et al. J infect Public Health 2011 ;4:200-6
*Al Khalidi J et al. Unpublished data
Treatment of HCV
2001-2011
Pegylated Interferon plus Ribavirin
combination was the standard
treatment of HCV regardless of
genotype until 2011
Sustained Virologic Responses By Genotype
100
80
% of patients
80
60
68*
45
40
20
0
G1
G2/3
G4
*Hasan F, et al. Am J Gastroenterol 2004;99:1733-1737
Interferon Plus Ribavirin Therapy
Limitations
20-60 % do not respond
Numerous side effects
Factors That Influence Response to
Interferon Based Therapy
Treatment regimen
Host factors
PEG-IFN
Ribavirin
DAA
Age, gender, race obesity,
co-morbidities
Genetic factors
(IL28B and ITPA)
Factors that affect
outcome
Disease features
Viral factors
Fibrosis, steatosis,
co-infection
(HBV, HIV)
Genotype / Subtype
Quasispecies / Resistance
Viral load
Most Important Factors that Influence
Treatment Outcome
HCV Genotype
IL 28 B Polymorphism
Degree of Fibrosis
HCV RNA level
Side Effects of PegIFN/Ribavirin
Fever
Myalgias
Hair loss
Depression
Anemia
Rash
“Interferon Man”
Many others !
Was it the Interferon Man ?
Contraindications of Pegylated
Interferon and Ribavirin
• De-compensated cirrhosis
• Coronary artery disease, heart failure, serious
dysrythmia
• Proliferative diabetic retinopathy
• Kidney transplant patients
• Renal impairment (ribavirin)
2011: Telaprevir and Boceprevir
for HCV Genotype 1
Sustained Virologic Response: Telaprevir plus Peg
Interferon Plus Ribavirin PR
74–79*
n/N =
PR48
T12/PR
166/361
683/903
*p<0.0001 T12/PR vs PR48 (79% versus 46%) in ADVANCE
SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window.
In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used
INCIVO (telaprevir) EU SmPC
SVR rates with boceprevir plus PR
versus PR alone
100
SVR (%)
80
63 *
66 *
PR48
BOC RGT
BOC44/PR48
137/363
233/368
242/366
60
38
40
20
0
n/N =
*p<0.001 for both boceprevir arms versus PR48
SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24.
If there was no such value, the follow-up Week value was carried forward
VICTRELIS (boceprevir) EU SmPC
Adverse Events with Telapravir and Bocepravir
Telaprevir
Telaprevir plus P/R
P/R
Pruritis
45-50%
28%
Nausea
40-43%
31%
56%
34%
Anemia
37-39%
19%
Diarrhea
28-32%
17%
11%
3%
Rash
Anorectal discomfort
Boceprevir
Anemia
50%
30%
35-43%
16%
Neutropenia
25%
19%
Nausea
46%
42%
Dysgeusia
Important Safety Information
Contraindicated Drugs and Other Precautions
for Telaprevir
Contraindicated
Potential for
increased toxicity
from concomitant
medication
Not recommended
Alfuzosin
(UroXatral)
Methylergonavine
(Methergine)
Amiodarone
(Cordarone, Pacerone)
Midazolam oral*
(Versed)
Dihydroergotamine
(D.H.E. 45 and Migranal)
Pimozide
(Orap)
Ergonvine
(Ergonovine Maleate)
Propafenone
(Rythmol)
Ergotamine
(Ergomar)
Flecainide
(Tambocor)
Lovastatin
(Altocor, Altoprev, Mevacor)
Quinidine
(Quinaglute Dura-Tabs,
Quinidex Extentabs,
Cardioquin, Quinora)
Budesonide inhaled
(Pulmicort Flexhaler,
Pulmicort Respules)
Use with caution
Alprazolam*
(Niravam, Xanax)
Atorvastatin* (Lipitor)
Nifedipine
(Adalat, Afeditab CR,
Nifediac, Nifedical,
Procardia)
Bosentan (Tracleer)
Nisoldipine (Sular)
Clarithromycin (Biaxin)
Posaconazole (Noxafil)
Colchicine§ (Colcrys)
Sildenafil for ED (Viagra)
Desipramine (Norpramin)
Tadalafil for ED (Cialis)
Digoxin* (Lanoxin)
Telithromycin (Ketek)
Diltiazem
(Cardizem, Dilacor,
Tiazac)
Tenofovir* (Viread)
Amlodipine* (Norvasc)
Colchicine†
(Colcrys)
Cyclosporine*‡
(Atopica, Gengraf, Neoral,
Sandimmune,
Fluticasone inhaled
(Flovent)
Salmeterol
(Serevent)
Sildenafil for PAH
(Revatio)
Sirolimus‡
(Rapamune)
Simvastatin
(Zocor)
Tacrolimus*‡
(Prograf )
Triazolam
(Halcion)
Tadalafil for PAH
(Adcirca)
Erthromycin
(E.S.P., Eryzole, Pediazole,
Sulfimycin)
Felodopine (Plendil)
Voriconazole
(Vfend)
Nicardipine (Cardene)
Itraconazole (Sporanox)
*These interactions have been studied; †Impaired renal/hepatic function; ‡No clinical data are available regarding the treatment of
Ketoconazole*
organ transplant patients with TRADENAME in combination with peg-IFN/RBV. Therefore, the use of TRADENAME in organ
transplant
(Feoris, Nizoral)
patients is not recommended; §Normal renal/hepatic function.
Lidocaine (Xylocaine)
Trazadone
(Desyrel, Oleptro)
Vardenafil
(Levitra, Staxyn)
Verapamil
(Calan, Covera, Isoptin,
Verelan)
Warfarin
(Coumadin, Jantoven,
Marfarin)
December 2013
Simeprevir and Sofosbuvir
Efficacy With Simeprevir + P/R in TxNaive GT1 Patients: Phase III Trials
• SMV + P/R for 12 wks followed by 12-36 wks of P/R
(placebo control)
Simeprevir + P/R
Placebo + P/R
100
SVR (%)
80
60
85
84
80
100
80
50
58
52
53
60
40
20
20
0
53
58
43
40
n/N =
82
419/ 133/
521 264
138/ 36/
165 83
49/ 23/
84 44
228/ 70/
267 133
Overall
GT1a
Without
Q80K
GT1a With
Q80K
GT1b
Jacobson I, et al. EASL 2013. Abstract 1425.
n/N =
0
29
188/ 60/
229 113
No Cirrhosis
18/ 5/
31 17
Cirrhosis
Simeprevir Is Well Tolerated
Bilirubin
20
SMV + P/R
P/R
10
Mean (µmol/L)
Mean (µmol/L)
30
200
Hemoglobin
180
SMV + P/R
P/R
160
140
120
100
0
0 2 4 8 12 16 20 24
36
Wks



48
0 2 4 8 12 16 20 24
Wks
Mild unconjugated hyperbilirubinemia → transporter
No anemia signal beyond P/R
Rash up to 25% (mild)
Manns M, et al. EASL 2013. Abstract 1413.
36
48
Efficacy With Sofosbuvir + P/R in Tx-Naive
GT1/4/5/6 Patients: Phase III Trials
• Single-arm study of sofosbuvir + P/R for 12 wks
SVR12 According to GT
100
89
96
SVR12 According to
Fibrosis Level
100
100
SVR12 (%)
SVR12 (%)
80
80
80
60
40
60
40
20
20
n/N = 261/292
0
92
GT1
27/28
GT4
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
7/7
GT5/6
0
252/273
43/54
No
Cirrhosis
Cirrhosis
Efficacy of Sofosbuvir in GT2
Treatment Naive[1]
Treatment Experienced[2]
12 wks of SOF + RBV
100
PegIFN/RBV
98
100
91
16 wks of SOF + RBV
100
96
82
80
78
80
SVR12 (%)
62
60
60
60
40
40
20
20
n/N =
0
58/59 44/54
10/11 8/13
n/N = 25/26 23/23
6/10
7/9
0
No Cirrhosis
Cirrhosis
1. Gane E, et al. EASL 2013. Abstract 5.
2. Jacobson I, et al. N Engl J Med. 2013;368:1867-1877.
No Cirrhosis
Cirrhosis
GT2
FDA Approved Indications for
Sofosbuvir
Treatment
Duration
HCV genotype 1 &4
Sofosbuvir+Peg-IFN+RBV
12 wks
HCV genotype 2
Sofosbuvir + RBV
12 wks
HCV genotype 3
Sofosbuvir + RBV
24 wks
HCV plus HCC
Decompensated Cirrhosis
Sofosbuvir + RBV
48 wks or Tx
DO NOT USE TELAPREVIR OR
BOCEPREVIR
The Future
Interferon Free Regimens
IFN-Free Therapy for Tx-Naive GT1 HCV
AVIATOR[1]
ABT-450/RTV + ABT-333
+ ABT-267 + RBV
12 wks
SVR12/24 (%)
100
96
24 wks
90
LONESTAR[2]
C-WORTHY
12-wk regimens[4]
AI443-014[3]
SOF/LDV FDC 8 wks
SOF/LDV + RBV 8 wks
SOF/LDV FDC 12 wks
100
95
95
100
Daclatasvir +
Asunaprevir +
BMS-791325
for 12 wks
100
92
MK-5172 + MK-8742 20 mg + RBV
MK-5172 + MK-8742 50 mg + RBV
MK-5172 + MK-8742 50 mg
100
80
80
80
80
60
60
60
60
40
40
40
40
20
20
20
20
n=
0
79
80
0
20
21
19
0
77
1. Kowdley K, et al. EASL 2013. Abstract 3. 2. Lawitz E, et al. AASLD 2013. Abstract 215.
3. Everson GT, et al. AASLD 2013. Abstract LB-1. 4. Lawitz E, et al. AASLD 2013. Abstract 76.
0
96
25
100
89
27
13
Is the demise of Hepatology imminent ?
• HCV cure rate approaching 95%
• HBV incidence declining rapidly due to
vaccination
• Treatment of HBV and HCV using direct acting
antivirals is safe, simple and can be handled by
internists.
• Alcoholic liver disease and NASH can be handled
by internists
• Only end stage liver disease and liver transplant
patients need specialty care ?