Advances in Management of Hepatitis C

Advances in management of Hepatitis
C (September 2016)
Dr. Arun Vasireddy
Dept of Medicine

Background
• High worldwide prevalence of HCV with regional differences
• Transmission by blood and associated risk factors
• High genomic variability of HCV
• Extrahepatic manifestations (especially B-cell proliferative
disorders)
• Multiple infections possible (lack of sterilizing immunity)
• Traditionally IFN containing regimens
• Newer DAAs
• IFN free regimens are soon going to be reality
• No prophylactic vaccine yet available

Epidemiology
• 185 million people are HCV infected
worldwide
• 3-4 million is the incidence/year
• HCV: Leading cause of liver
transplantation
• 27% of cirrhosis and 25% of liver
cancer can be attributed to hepatitis C
worldwide
Annual 1.75
million deaths
due to liver
cancer and
cirrhosis1
1.31 million
attributed to
chronic viral
infection 1
Annual 350,000
deaths due to all
HCV-related
causes 1
1. Abstract 23; Benjamin C. Cowie et al. Presented at the 64th AASLD meeting, Nov 1-5, 2013; Washington,
DC.
2. J Hepatol 2006;45:529-538.
3. Hepatology 2013;57:1333-1342
4. J. Biosci. 2008;33 465–473.
5. Indian J Gastroenterol 1998;17:100 –3.

Global HCV prevalence among adults

Relative genotype prevalence of HCV genotypes
Hepatology. 2014 Jul 28. doi: 10.1002/hep.27259.
HCV genotype 1 is the most prevalent worldwide, comprising 83.4 million cases (46.2% of all
HCV cases), approximately one third of which are in East Asia
Genotype 3 is the next most prevalent globally (54.3 million, 30.1%)

Indian Epidemiology
• The prevalence of HCV infection in India is estimated at between
0.5% and 1.5% (15-18 million)
• It is higher in the north-eastern part, tribal populations and Punjab,
areas that may represent HCV hotspots, and is lower in the western
and eastern parts of the country
– Genotype 3 is the most common HCV genotype in India (accounting
for 54–80% of cases), followed by genotype 1
– Genotype 1 has been reported more commonly from southern India and
there are increasing reports of genotype 4 from India.
Journal of Clinical and Experimental Hepatology 2014; 4(2):106–116.

Structure of HCV
•HCV genome has one 9.6 kb single-stranded
RNA
•The viral RNA codes a precursor polyprotein of
approximately 3,000 amino acid residues
•During viral replication, the polyprotein is
broken down by viral as well as host enzymes
into three structural proteins (core, E1, E2) and
seven non-structural proteins (p7/NS1, NS2,
NS3, NS4A, NS4B, NS5A, and NS5B)

Natural history of HCV mono-infection
over 10-15 years
Clin Liver Dis. 2005;9:383-398
Eur J Gastroenterol Hepatol. 1996;8:324-328. Hepatology. 2002;36(suppl):S1-S2.
Hepatology. 2002;36(suppl):S35-S46.
Ann Intern Med. 2000;132:296-305. Gastroenterology. 1997;112:463-472.

HCV: Major epidemic that is untreated

Why every patient cant be on Peg IFN-RBV
therapy
• In some patients
– IFN or RBV contraindicated
– HCV may spontaneously
resolve
– Fibrosis may be absent or
nonprogressive
– Injections may be intolerable
– Autoimmune conditions or
mental illness may be
exacerbated
– Cost/benefit evaluation
• Peg-IFN toxicity
– Flu-like and GI symptoms
– Cytopenias (thrombocytopenia,
neutropenia)
– Depression (including suicidal
ideation), somnolence
– Autoimmune disease
– Hair loss
• RBV toxicity
– Cardiovascular disease
– Hemolytic anemia
– Risk of fetal malformations
– Renal failure
Semin Liver Dis. 1999;19(suppl 1):67-75.

Challenges with existing Peg IFN-RBV therapy
• Genotype 1 HCV infections are more severe and are less responsive to
Peg/Ribavirin therapy than either type 2 or 3 infections
• Approximately 25-35% of G1 treatment naïve patients and 50-60% of G1
HCV patients who failed to respond to a first course of treatment with
PEG-IFN and RBV do not achieve SVR and are not cured of HCV infection with
even triple combination with telaprevir/boceprevir
• Cure—sustained virologic response (SVR) achieved in only ~40-50% of
genotype1 patients and 70-80% of genotype 2 or 3 patients

Targets for directly acting antivirals in the HCV
Liver International 2012; 32, Supplement
s1:88–102.

Overview of DAAs
NS3/4A NS5A NS5B
Function Serine Protease Component of HCV
Replication Complex
RNA-dependent RNA
polymerase
Drugs Covalent
Boceprevir
Telaprevir
Non-covalent
Faldaprevir
Simeprevir
ABT-450
Asunaprevir
MK-5172(Grazoprevir)
Ledipasvir
Daclatasvir
Ombitasvir
MK-8742 (Elbasvir)
PPI-668
Nucleos(t)ide analogs
Sofosbuvir
ACH-3422
Non-nucleoside
BMS-791325 /Beclabuvir
Dasabuvir
Deleobuvir
C E1 E2
p
7 NS2 NS3 NS4A NS4B NS5A NS5B
Core Envelope Glycoproteins Protease Serine
Protease
Helicase Serine
Protease
Cofactor
RNA-dependent
RNA polymerase
Component of
HCV Replicase

Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting,
April 27-28, 2011, Silver Spring, MD.
IFN
6 mos
PegIFN/ RBV
12 mos
IFN
12 mos
IFN/RBV
12 mos
PegIFN
12 mos
2001
1998
2011
Standard
IFN
RBV
PegIFN
1991
DAAs
PegIFN/
RBV/
DAA
IFN/RBV
6 mos
6
16
34
42 39
55
70+
0
20
40
60
80
100
DAA
+ RBV
± PegIFN
90+
2013
The Good News

Treatment Naïve Patients
Genotype 1
Treatment History Cirrhosis Status IFN Eligibility Preferred Regimen
Naive
Non – Cirrhotic or
Cirrhotic
Eligible Sofosbuvir + PEG-IFN/RBV x 12
weeks
Non – Cirrhotic Ineligible Sofosbuvir + RBV x 24 weeks or
Sofosbuvir + Simeprevir +/- RBV x
12 weeks
(NOT FDA Approved)
Cirrhotic Ineligible Sofosbuvir + Simeprevir +/- RBV x
12 weeks
(NOT FDA Approved)
Abbreviations: PEG-IFN = Peginterferon; RBV = Ribavirin
Dosages: PEG-IFN alfa-2a 180mcg subcutaneously weekly or Peg-IFN alfa-2b 1.5 mcg/kg subcutaneously weekly; RBV
weight based 1,000 mg (<75kg) or 1,200 mg (>75kg) orally daily in two divided doses with food; Simeprevir 150 mg orally
with food; Sofosbuvir 400mg orally daily

Genotype 2
Naive
Non-Cirrhotic Either Sofosbuvir + RBV x
12 weeks
Cirrhotic Either Sofosbuvir + RBV x
16 weeks

Genotype 3
Naive
Non-Cirrhotic or
Cirrhotic
Eligible Sofosbuvir + RBV x
24 weeks or
Sofosbuvir + PEG-
IFN/RBV x 12 weeks
Non-Cirrhotic or
Cirrhotic
Ineligible Sofosbuvir + RBV x
24 weeks

Genotype 4,5 or 6
Naive
Non-Cirrhotic or
Cirrhotic
Eligible Sofosbuvir + PEG-
IFN/RBV x 12 weeks
Non-Cirrhotic or
Cirrhotic
Ineligible Sofosbuvir + RBV x
24 weeks

TREATMENT GUIDELINES
- TREATMENT FAILURE CASES

Treatment Failure Cases
Genotype 1
Recommended regimens for patients with HCV genotype 1a or 1b
infection who have compensated cirrhosis, in whom prior PEG-IFN and
RBV treatment has failed.
– Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400
mg) for 24 weeks is recommended for patients with HCV genotype 1a
or 1b infection who have compensated cirrhosis, in whom prior PEG-
IFN and RBV treatment has failed OR
– Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without
weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24
weeks is recommended for patients with HCV genotype 1 infection,
regardless of subtype, in whom prior PEGIFN and RBV treatment has
failed.

Genotype 2
Recommended regimen for patients with HCV genotype 2 infection, in whom prior
PEG-IFN and RBV treatment has failed.
– Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200
mg [>75 kg]) for 12 weeks to 16 weeks is recommended for patients with HCV
genotype 2 infection, in whom prior PEG-IFN and RBV treatment has failed.
Alternative regimen for patients in whom previous PEG-IFN and RBV treatment
failed who have HCV genotype 2 infection and are eligible to receive IFN.
– Retreatment with daily sofosbuvir (400 mg) and weight-based RBV (1000 mg
[<75kg] to 1200 mg [>75 kg]) plus weekly PEG-IFN for 12 weeks is an
alternative for patients in whom previous PEG-IFN and RBV treatment failed
who have HCV genotype 2 infection and are eligible to receive IFN.

Genotype 3
Recommended regimen for patients with HCV genotype 3 infection in whom prior
PEG-IFN and RBV treatment has failed.
– Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200
mg [>75 kg]) for 24 weeks is recommended for treatment of HCV genotype 3
infection in patients in whom prior PEG-IFN and RBV treatment has failed.
Alternate regimen for patients with HCV genotype 3 who are eligible to receive
IFN, in whom prior PEG-IFN and RBV treatment has failed.
– Retreatment with daily sofosbuvir (400 mg) and weight-based RBV (1000 mg
[<75kg] to 1200 mg [>75 kg]) plus weekly PEG-IFN for 12 weeks is an
alternative for patients with HCV genotype 3 infection who are eligible to
receive IFN, in whom prior PEG-IFN and RBV treatment has failed.

Genotype 4
Recommended regimen for patients with HCV genotype 4 infection in whom
prior PEG-IFN and RBV treatment has failed
– Daily sofosbuvir (400 mg) for 12 weeks and daily weight-based RBV (1000
mg [<75kg] to 1200 mg [>75 kg]) plus weekly PEG-IFN for 12 weeks is
recommended for retreatment of IFN-eligible patients with HCV genotype
4 infection, in whom prior PEG-IFN and RBV treatment has failed. OR
– Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to
1200 mg [>75 kg]) for 24 weeks is recommended for retreatment of
patients with HCV genotype 4 infection, in whom prior PEG-IFN and RBV
treatment has failed.
Genotype 5 and 6
Recommended regimen for patients with HCV genotype 5 infection in whom
prior treatment has failed.
– Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to
1200 mg [>75 kg]) plus weekly PEG-IFN for 12 weeks is recommended for
patients with HCV genotype 5 and 6 infection in whom prior treatment
has failed.

- PATIENTS WITH DECOMPENDATED
CIRRHOSIS

Patients with Decompensated Cirrhosis
Genotype 1 and 4
For patients with decompensated cirrhosis in whom prior sofosbuvir-
based treatment has failed, daily fixed-dose combination ledipasvir (90
mg)/sofosbuvir (400 mg) and RBV (initial dose of 600 mg, increased as
tolerated) for 24 weeks.
Genotype 2 and 3
Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to
1200 mg [>75 kg]) (with consideration of the patient’s creatinine clearance
rate and hemoglobin level) for up to 48 weeks is recommended for
patients with HCV genotype 2 or 3 who have decompensated cirrhosis.
This regimen should be used only by highly experienced HCV practitioners.

- PATIENTS WITH RECURRENT HCV INFECTION POST LIVER
TRANSPLANT

Recurrent Post Liver Transplantation
• Genotype 1 or 4
– Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400
mg) with weight based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg])
for 12 weeks is recommended for patients with HCV genotype 1 or 4
infection in the allograft, including compensated cirrhosis.
• Genotype 2
– Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg]
to 1200 mg [>75 kg]) for 24 weeks is recommended for patients with
HCV genotype 2 in the allograft, including compensated cirrhosis
• Genotype 3
– Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg]
to 1200 mg [>75 kg]) for 24 weeks is recommended for treatment-
naive patients with HCV genotype 3 infection in the allograft,
including compensated cirrhosis.

- PATIENTS WITH HEPATOCELLULAR
CARCINOMA

Patients with Hepatocellular Carcinoma
Genotype Treatment
History
Cirrhosis Status IFN
Eligible
Preferred Regimen
1,2,3 or 4 Naïve or
Experienced
Hepatocellular
carcinoma
Either Sofosbuvir + RBV x 24-48
weeks or until liver
transplant, whichever occurs
first
Dosages:
Sofosbuvir – 400mg once daily with or without food
RBV(Ribavirin) – Weight based 1000mg (<75 kg) or 1200mg (>75kg)
orally daily in two divided doses with food

Summary
Dosages: PEG-IFN alfa-2a 180mcg subcutaneously weekly or Peg-IFN alfa-2b 1.5
mcg/kg subcutaneously weekly; RBV weight based 1,000 mg (<75kg) or 1,200 mg
(>75kg) orally daily in two divided doses with food; Sofosbuvir 400mg orally daily
with or without food

Rationale for IFN-Free Direct-Acting
Antiviral Therapy for HCV
• Drawbacks of IFN-based Therapy
– Challenging tolerability
– High percentage of patients are ineligible for IFN
– Long duration of therapy
– Low SVR rates compared to modern all-oral regimens
• PR: ~40-50% in treatment-naïve patients
• Triple therapy PR + boceprevir or telaprevir: ~70%
– Many patient-specific and virus-specific factors affecting eligibility
or treatment response (Race, IL28B, cirrhosis, prior treatment, etc)
– Development of resistance
– Requires injection

Not All Direct-Acting Antivirals are
Created Equal
Characteristic
Protease
Inhibitor*
Protease
Inhibitor**
NS5A
Inhibitor
Nuc
Polymerase
Inhibitor
Non-Nuc
Polymerase
Inhibitor
Resistance
profile
Pangenotypic
efficacy
Antiviral
potency
Adverse
events
Good profile Average profile Least favorable profile
*First generation. **Second generation.

Future HCV treatment
Clinical and Translational Medicine 2013, 2:9
IFN - sparing
regimens
IFN /RBV - free
regimens

Newer DAA’s globally for HCV
treatment
IFN free DAA combinations
• Sofosbuvir +ledipasvir FDC ± RBV (Genotype 1 )
• Sofosbuvir + Simeprevir ± RBV (Genotype 1 )
• AbbVie's 3D regimen : paritaprevir (ABT-450) boosted with
ritonavir , ombitasvir as FDC and dasabuvir ± RBV (Genotype 1 )
• Grazoprevir + Elbasvir ± RBV (Genotype 1 ) (pending approval )
• Sofosbuvir + Daclatasvir ± RBV (Pangenotypic) (pending approval
in USA)
• Sofosbuvir + GS 5816 ± RBV (Pangenotypic) (pending approval in
USA)

FISSION Trial: Sofosbuvir + RBV
(12 weeks) : GT2 &3
Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5.
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
0
20
40
60
80
100
SVR12,%Patients
Genotype 2
98%
91%
82%
62%
No Cirrhosis Cirrhosis
0
20
40
60
80
100
SVR12,%Patients
Genotype 3
61%
71%
34%
30%
Sofosbuvir + RBV
PR
n=59 n=54 n=11 n=13 n=145 n=139 n=38 n=37
Sofosbuvir + RBV
PR

POSITRON: Sofosbuvir + RBV for 12 Weeks
interferon-ineligible, -intolerant, or -unwilling
patients
Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61.
Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
0
20
40
60
80
100
SVR12(%)
Genotype 2
92% 94%
No Cirrhosis
(n=92)
Cirrhosis
(n=17)
0
20
40
60
80
100
Patients(%)
Genotype 3
68%
21%
No Cirrhosis
(n=84)
Cirrhosis
(n=14)
SVR12 rate was 0% in the placebo arm.

FUSION Trial: SVR12 Rates by Genotype and
Cirrhosis
Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6.
Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
0
20
40
60
80
100
Patients(%)
Genotype 2
96%
60%
100%
78%
0
20
40
60
80
100
Patients(%)
Genotype 3
37%
63%
19%
61%
Sofosbuvir + RBV
12 weeks
16 weeks
Sofosbuvir + RBV
12 weeks
16 weeks
n=26 n=23 n=10 n=9 n=38 n=40 n=26 n=23
Failed prior IFN-based therapy
30% with cirrhosis

VALENCE Trial: Sofosbuvir + RBV
Zeuzem S, et al. Hepatology. 2013;58(suppl 1):733A-734A. Abstract 1085.
0
20
40
60
80
100
SVR12(%)
93
100
85
91
97
Overall
94 92
87
Genotype 2 (12 weeks)
Genotype 3 (24 weeks)
Noncirrhotic
60
88
Treatment-Naive
Cirrhotic Noncirrhotic Cirrhotic
Treatment-Experienced
No resistance detected in patients with relapse.
n=73 n=250 n=30 n=92 n=2 n=13 n=33 n=100 n=8 n=45
Treatment-naïve or experienced
Approximately 20% with cirrhosis

Conclusions
• Most GT3 patients will be able to be treated with 24 wks of
SOF/RBV
• GT3, treatment-experienced, cirrhotic patients most
challenging group to treat with all-oral regimens
– Experts recommend 12 wks of SOF + pegIFN/RBV in short
term

Sofosbuvir +Ledipasvir FDC
LDV/SOF ±RBV for 8, 12 or 24 weeks in GT 1 patients

All-Oral 12-Week Combination Treatment With Daclatasvir and
sofosbuvir in Patients Infected With HCV Genotype 3: ALLY-3
Phase 3
a Cirrhosis status determined in 141 patients by liver biopsy (METAVIR F4), FibroScan (> 14.6 kPa), or FibroTest score ≥ 0.75 and APRI (aspartate aminotransferase to
platelet ratio index) > 2.
b Cirrhosis status for 11 patients was inconclusive (FibroTest score > 0.48 to < 0.75 or APRI > 1 to ≤ 2). Hepatology. 2015;61(4):1127-35.

SVR ±RBV with paritaprevir, ombitasvir+ dasabuvir for
12 weeks in GT 1 patients

Paritaprevir +ombitasvir+ dasabuvir SVR12 in GT 1a
cirrhosis TN and TE

IFN-free therapy combinations high efficacy
Genotype 1

Recommendations from the AASLD-IAS –IDSA and
EASL guidelines based on new DAAs

Summary
• Multiple all-oral DAA regimens will be available over the next
12-18 mos:
– Dual and triple DAA regimens yield the highest SVR rates
(90%+) ever described
– Treatment duration of 12 wks (maybe shorter)
– Well tolerated across all populations
– Importance of RBV varies with regimen and virologic
characteristics
– Preliminary data indicate that traditionally difficult to cure
populations (cirrhosis, previous PI failures) will benefit
greatly from IFN/RBV-free DAA regimens

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