HEPATITIS C

TREATMENT:
AT A NEW EDGE
Presented by:
Adilah Mohd Fazli
Shirlyn Tan
(25 May 2018)
 INTRODUCTIO
N
 Hepatitis C is a liver disease caused by the hepatitis C virus
 acute & chronic hepatitis

 A bloodborne virus -> injection drug use, unsafe injection

practices, unsafe health care, and the transfusion of
unscreened blood and blood products.

 Globally, an estimated 71 million people have chronic

hepatitis C infection.

 Approximately 399 000 people die each year from hepatitis

C, mostly from cirrhosis and hepatocellular carcinoma.

http://www.who.int/en/news-room/fact-sheets/detail/hepatitis-c
 INTRODUCTIO
N

Introduction

- Usually asymptomatic - 60-80% develop - 15-30% develop

- 15-45% spontaneously chronic HCV infection liver cirrhosis within
clear the virus within 6 20 years
months without
treatment
 INTRODUCTIO
N
 HCV genotype- determines antiviral regimen, dose
and duration

 HCV family of viruses: at least 6 genotypes

 The most common in Malaysia: Genotype 1 & 3

Hepatitis C screening, testing & treatment Guideline, Ministry of Health Malaysia Putrajaya, 1 st Edition October 2017
 TYPES OF
DAAs

Direct-acting Antivirals (DAAs)

 Molecules that target specific nonstructural
proteins of the virus  disruption of viral
replication and infection.

 There are four classes of DAAs, which are defined

by their mechanism of action and therapeutic
target.
 Classes of DAAs Drugs
NS3/4A Protease Inhibitors Simeprevir
Glecaprevir
Grazoprevir
Paritaprevir
Voxilaprevir

NS5B nucleoside polymerase inhibitors Sofobuvir

NS5B non-nucleoside polymerase inhibitors Dasabuvir
NS5A inhibitors Daclatasvir
Elbasvir
Ledispasvir
Ombitavir
Pibrentasvir
Velpatasvir

Fixed-doses Combination:
Ombitavir/Paritaprevir/Ritonavir (Viekira)
Sofobuvir/Ledispasvir (Harvoni)
Grazoprevir/Elbasvir (Zepatier)
Sofobuvir/Velpatasvir (Epclusa)
 
±Ribavirin
 INDICATIONS
1. All treatment-naive and treatment-experienced patients
with compensated or decompensated chronic liver disease
( CPS A and B) due to HCV
2. Treatment should be considered without delay in:
 Patients with including decompensated (Child-Pugh B)
cirrhosis,
 Patients with HCV related conditions (e.g. symptomatic
vasculitis associated with HCV-related mixed
cryoglobulinaemia, HCV immune complex-related nephropathy
and non-Hodgkin B cell lymphoma),
 Patients with HCV recurrence after liver transplantation, and
 Individuals at risk of transmitting HCV (active PWID, men who
have sex with men with high risk sexual practices, women of
childbearing age who wish to get pregnant, haemodialysis
patients and incarcerated individuals)
 INDICATIONS

3. Treatment is not recommended in patients with

limited life expectancy due to non-liver-related
comorbidities.

4. All treatment-naive and treatment-experienced

patients with compensated or decompensated
chronic liver disease related to HCV, who are
willing to be treated and who have no
contraindications to treatment
 DURATION

Duration of Treatment
 AASLD 2017 EASL 2016
Genotype 1a No Cirrhosis Treatment naïve 12 weeks 12 weeks
Treatment Exp 12 weeks 12 weeks with Ribavirin
PR or 24 without Ribavirin
Compensated Treatment naive 24 weeks with or 12 weeks
Cirrhosis without Ribavirin
Treatment 24 weeks with our 12 weeks with Ribavirin
experience without Ribavirin or 24
Genotype 1 b No Cirrhosis Treatment naïve 12 weeks 12 weeks
Treatment Exp 12 weeks 12 weeks
Compensated Treatment naïve 24 weeks with our 12 weeks
Cirrhosis without Ribavirin
Treatment Exp 24 weeks with our 12 weeks
PR without Ribavirin
Genotype 3 No Cirrhosis Treatment naïve 12 weeks 12 weeks
Treatment Exp 12 weeks 12 weeks with Ribavirin
PR or 24
Compensated Treatment naïve 24 weeks with or 24 weeks
Cirrhosis without Ribavirin
Treatment Exp 24 weeks with our 24 weeks
PR without Ribavirin
 GOALS
1. To eradicate Hepatitis C virus (HCV) & CURE the infection.

2. To reduce all-cause mortality and liver- related complications

including fibrosis, cirrhosis, end-stage liver disease and
hepatocellular carcinoma (HCC).

3. To prevent transmission of HCV infection.

4. To prevent or improve extra-hepatic manifestations like

cryoglobulinemic vasculitis, diabetes and etc.

5. To improve quality of life including physical, emotional, and

social health.
 SOFOSBUVIR

 HCV nucleotide polymerase NS5B inhibitor.

 400mg (one tablet) once daily .
 With or without food.
 SOFOSBUVIR
MOA

Activation of sofosbuvir in
liver. CatA -human cathepsin
A; CES1- carboxylesterase 1;
Hint1 - histidine triad
nucleotide-binding protein 1;
NDPK – nucleoside
diphosphate kinase; UMP–
CMP kinase-uridine
monophosphate–cytidine
monophosphate kinase
 SOFOSBUVIR

PK Profile
 Approximately 80% of sofosbuvir is renally excreted,
whereas 15% is excreted in feces.
 Used in patients with eGFR of > 30ml/min/1.73m2. Latest
EASL 2018 states that can be used with cautious in eGFR
of less than 30ml/min/1.73m2 and even haemodialysis
patients.
 SOFOSBUVIR

Drug-drug Interactions
 Not metabolized by cytochrome P450, but is transported by
P-gp.
 Sofosbuvir should not be administered with known P450
inducers , such as rifampin, carbamazepine, phenytoin or St.
John’s wort. Other potential interactions may occur with
rifabutin, rifapentine and modafinil.
 Contraindicated in patients who are being treated with the
anti-arrhythmic amiodarone due to the risk of life-
threatening arrhythmias.
 DACLATASVIR

 First-ever approved HCV NS5A replication complex

inhibitor with pangenotypic activity.
 The dose of 60 mg (one tablet) or 30 mg (one tablet)
when a reduced dose is needed, once daily dose.
 With or without food.
 Cannot be cut or crushed.
 DACLATASVIR

MOA
 DACLATASVIR

PK Profile
 Daclatasvir is highlyprotein bound to plasma
proteins and is unlikely to be removed by dialysis.
 No dosage adjustment is required for patients with
any degree of renal impairment
 DACLATASVIR

Drug-drug Interactions
 May interact with other drugs e.g. anti-TB, antibiotics,
herbals containing St John Worts
 Contraindicated in patients who are being treated with
strong inducers of CYP3A, including phenytoin,
carbamazepine and rifampin
 Dose adjustment required in patient with Hep C HIV co-
infection
 CYP3A enzyme inducer  Efavirenz requires Daclatasvir 90 mg
 CYP3A enzyme inhibitor  Ritonavir requires Daclatasvir 30 mg
 DACLATASVIR

Common Side Effects

 Generally well tolerated, not known side effects (SE) of
its own.
 The most common SEs combination Sofosbuvir and
Daclatasvir:
 fatigue, nausea and headache ( 10% )
 RIBAVIRIN
 Used for combination with Sofosbuvir and Daclatasvir
 The dose = 1000 mg/ day for body weight of < 75 kg or
1200 mg/day, for ≥ 75 kg, split in two administrations.
 Dose adjustment is needed in patients with severe renal
insufficiency or ESRD.
 In decompensated cirrhosis, ribavirin can be started at the
dose of 600 mg daily and the dose subsequently adjusted
depending on tolerance.
 Black box FDA warning : SEs may be severe and serious.
 SEs : Flu like symptoms, headache, fatigue, mood changes.
 Serious SEs : anemia , birth defect, suicidal thoughts.
 RIBAVIRIN

Modifications of Ribavirin dose

Haemoglobin level No cardiac disease Stable cardiac disease
(g/dL)
< 10 .0 Reduce to 600 mg / day Decrease ≥ 2g/dL during 4 weeks
period : reduce to 600 mg/ day
(permanent dose reduction)
< 8.5 Discontinue Hb < 12g/dL despite 4 weeks in
reduced dose: discontinue
 Please refer to www.hep-
druginteractions.org for
drug-drug interaction and
EASL HCV Advisor
(application can be
downloaded for Apple
and Android user) for
further reference
JOURNAL REVIEW
 Study Design & Setting
ALLY-1 Multicenter, prospective, open-label, phase 3 study of daclatasvir plus
sofosbuvir plus ribavirin in treatment-naïve and treatment-experienced
patients with advanced cirrhosis or post-liver transplant HCV recurrence
Five centers in the United States
ALLY-2 Phase 3, open label study of daclatasvir (DCV) plus sofosbuvir (SOF) in
treatment-naïve or experienced, chronic HCV GT 1-4 and HIV coinfection
Multiple Centers in the United States
ALLY-3 Phase 3 open-label two-cohort study of daclatasvir (DCV) plus sofosbuvir
(SOF) in treatment-naïve or experienced, chronic HCV GT 3
Multiple centers in the United States
ALLY-3+ Phase 3 open-label randomized trial of daclatasvir (DCV) and sofosbuvir
(SOF) plus ribavirin (weight-based dosing) for 12 versus 16 weeks in
treatment-naïve or experienced, chronic HCV GT 3 with advanced fibrosis
or compensated cirrhosis
10 clinical centers in France and Australia

All study Outcome Measure: Primary = SVR 12

RESULTS: ALLY-1
 Results: ALLY-1
SVR12 Results for Advanced Cirrhosis Cohort by
Genotype

Poordad F, et al. Hepatology. 2016;63:1493-505.

 Results: ALLY-1
SVR12 Results for Advanced Cirrhosis Cohort by
Child-Pugh Class

Poordad F, et al. Hepatology. 2016;63:1493-505.

 Results: ALLY-1
SVR12 Results for Post-Liver Transplant Cohort
by Genotype

Poordad F, et al. Hepatology. 2016;63:1493-505.

RESULTS: ALLY-2
 Results: ALLY-2
SVR12 Results for Genotype 1

Wyles DL, et al. N Engl J Med. 2015;373:714-25.

 Results: ALLY-2
SVR12 Results for Genotype 1
by Liver Status

Wyles DL, et al. N Engl J Med. 2015;373:714-25.

 Results: ALLY-2
SVR12 Results for Genotype 2

Wyles DL, et al. N Engl J Med. 2015;373:714-25.

 Results: ALLY-2
SVR12 Results for Genotype 3

Wyles DL, et al. N Engl J Med. 2015;373:714-25.

 Results: ALLY-2
SVR12 Results for Genotype 4

Wyles DL, et al. N Engl J Med. 2015;373:714-25.

RESULTS: ALLY-3
 Results: ALLY-3
SVR12 in all subjects

Nelson DR, et al. Hepatology 2015;61:1127-35.

 Results: ALLY-3
SVR12 based on baseline characteristics

• No notable differences in SVR12 between baseline characteristics

Nelson DR, et al. Hepatology 2015;61:1127-35.
 Results: ALLY-3
SVR12 based on cirrhosis status

• SVR12 rates were higher in patients without cirrhosis

Nelson DR, et al. Hepatology 2015;61:1127-35.
 Results: ALLY-3 on Safety & Tolerability

• Serious AE -> GI hemorrhage, not related to study medication

RESULTS: ALLY-3+
 Results: ALLY-3+
SVR12 in all subjects

Leroy V, et al. Hepatology 2016;63:1430-41.

 Results: ALLY-3+
SVR12 in adv. fibrosis vs cirrhosis

• Adv. Fibrosis: SVR12 in 100% of patients

• Cirrhosis: SVR12 in 86% (overall) of patients
• Treatment-experienced cirrhosis: SVR12 in 87% (overall) of patients
 Results: ALLY-3+ Safety & Tolerability

• 5 serious AE: somnolence, pneumonia, basal cell carcinoma, atherosclerosis

& 1 death from dilated cardiomyopathy -> all not related to treatment
 Conclusion
ALLY-1 The pan-genotypic combination of daclatasvir, sofosbuvir,and ribavirin was
safe and well tolerated. High SVR rates across multiple HCV genotypes were
achieved by patients with post-liver transplant recurrence or advanced
cirrhosis
ALLY-2 Among previously untreated HIV–HCV coinfected patients receiving
daclatasvir plus sofosbuvir for HCV infection, the rate of sustained virologic
response across all genotypes was 97.0% after 12 weeks of treatment and
76.0% after 8 weeks
ALLY-3 A 12-week regimen of daclatasvir plus sofosbuvir achieved SVR12 in 96% of
patients with genotype 3 infection without cirrhosis and was well tolerated.
ALLY-3+ The all-oral regimen of daclatasvir-sofosbuvir-ribavirin was well tolerated
and resulted in high and similar SVR12 after 12 or 16 weeks of treatment
among genotype 3-infected patients with advanced liver disease,
irrespective of prior HCV treatment experience
Take home message
 Currently, Daclatasvir & Sofosbuvir are available
for the treatment of Hepatitis C in Malaysia
 In HTAR, we have allocation to treat 60 patients
 It is a once daily dose regimen for at least 12
weeks
 Ribavirin is not available in HTAR but stock can
be obtained from H. Selayang if needed
Counseling points
 Adherence
 Missed dose management
 Administration time
 Drug Storage: room temperature (Below 30’C)
 Patient diary card to record each drug intake
 Bring back all balance medications and empty
bottle for each visit
 Use of any medication or herbal/supplement
product not prescribed by a licensed physician is
prohibited
THANK YOU!!