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Hepatitis C (HCV):
A Look at Current (and Future!) Treatments
Elva Angelique Van Devender, Ph.D., Pharm.D., BCPS
Legacy Good Samaritan Emergency Department
June 2014
Learning Objectives
Understand the prevalence of hepatitis C (HCV) in the United
States
Describe the natural history of HCV infection
Explain the rationale and goals of antiviral treatment of HCV
Identify the approved FDA antiviral treatments available for
HCV infection
Understand the pros and cons of the newest antiviral
therapies available (and in the pipeline!) for HCV treatment
10/2/2014 2
October 2, 2014 3
Background
Hepatitis C (HCV) is an infection caused by a virus that
attacks the liver and leads to inflammation.
170 million infected worldwide (highest in Asia and Africa—
3% of population)
3-4 million infected in the USA—1.6% of population
Background
Genotype: 6 genotypes worldwide
> Genotype 1
Most common in USA
Lowest response rates
Longest treatment duration
Initial symptoms
> Asymptomatic (~80% of people initially)
> Arthralgias/ myalgias
> Paresthesias
> Pruritus
> Sensory neuropathy
10/2/2014 4
Evolution of HCV Infection
10/2/2014 5
HCV Now Exceeds HIV as Cause of
Death in USA
10/2/2014 6
Goals of Therapy
To achieve sustained eradication of HCV (i.e. sustained
virologic response, or SVR)
To prevent progression to cirrhosis, hepatocellular carcinoma
(HCC), and decompensated liver disease necessitating liver
transplantation
10/2/2014 7
Ideal Regimen for HCV
high potency
little resistance
tolerable
once daily
shorter duration
few drug interactions
lower cost
10/2/2014 8
FDA Approved Treatments
Monotherapy
IFN-2a
IFN-2b
PEG-IFN 2a
PEG-IFN 2b
In combination with other
agents:
Sofosbuvir
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Combination Therapy
IFN-2a + Ribavirin
IFN-2b + Ribavirin
PEG-IFN 2a + Ribavirin
PEG-IFN 2b + Ribavirin
PEG-IFN + ribavirin +
either:
Boceprevir
Telaprevir
Simeprevir
Current HCV Treatments
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Peg-interferon
Ribavirin
Boceprevir
Telepravir
Simepravir
Sofosbuvir
Current and Pipeline HCV Treatments
and HCV Genotypes
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Current and Pipeline HCV Treatments
and HCV Genotypes
10/2/2014 12
Evolution of HCV Treatment Through
2001
10/2/2014 13
Comparison of 1st Generation Protease
Inhibitors
10/2/2014 14
Previous Side Effects of Treatment Gastrointestinal
Anorexia
Nausea/vomiting
Diarrhea/ constipation
Pancreatitis
Endocrine/metabolic
Thyroid
Diabetes
Hyperuricemia
Pulmonary
Cough
Dyspnea on exertion
Interstitial lung disease
Pulmonary infiltrates
Pneumonitis/Pneumonia
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Teratogenicity (ribavirin)
Neuropsychiatric
Depression
Irritability
Insomnia
Suicidal ideation
Cardiovascular
CAD risks with anemia
Increased triglycerides
Blood/bone marrow toxicity
Anemia
Leukemia/neutropenia
Thrombocytopenia
Ophthalmic
Retinal hemorrhages
Cotton wool spots
Flu-like symptoms
(interferon)
Fatigue
Fever/chills
H/A
Myalgia
Cutaneous
Injection-site
reactions
Rash/pruritus
Alopecia
Contraindications to Therapies That
Include Interferon/ Ribavirin
Major uncontrolled depressive illness
Solid organ transplant (renal, liver, lung)
Autoimmune hepatitis or other autoimmune condition known
to be exacerbated by interferon
Untreated thyroid disease
Pregnant or unwilling to comply with adequate contraception
Severe concurrent medical disease
Age less than 2 years
Known hypersensitivity to drugs used to treat HCV
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Pipeline of Novel Agents Protease inhibitors
telaprevir
boceprevir
simeprevir
faldaprevir
vaniprevir
narlaprevir
danoprevir
GS-9256
BMS-650032
ACH-1625
VX-500
BIT-225
ABT-450
10/2/2014 17
NS5A inhibitors
daclatasvir
ledipasvir
BMS-824383
PPI-461
ABT-267
Entry inhibitors
ITX-5061
NS4B inhibitors
Clemizole
cyclophilin inhibitor
alisporivir
Polymerase inhibitors
sofosbuvir
filibuvir
ANA-598
BI-207127
BMS-791325
tegobuvir
RG7129
VX-222
VX-759
VX-916
TMC-649128
MK-3281
INX-189
IDX-375
ABT-072
ABT-333
miR-122 as target
miravirsen
Pipeline of Novel Agents Protease inhibitors
telaprevir
boceprevir
simeprevir
faldaprevir
vaniprevir
narlaprevir
danoprevir
GS-9256
BMS-650032
ACH-1625
VX-500
BIT-225
ABT-450
10/2/2014 18
NS5A inhibitors
daclatasvir
ledipasvir
BMS-824383
PPI-461
ABT-267
Entry inhibitors
ITX-5061
NS4B inhibitors
clemizole
cyclophilin inhibitor
alisporivir
Polymerase inhibitors
sofosbuvir
filibuvir
ANA-598
BI-207127
BMS-791325
tegobuvir
RG7129
VX-222
VX-759
VX-916
TMC-649128
MK-3281
INX-189
IDX-375
ABT-072
ABT-333
miR-122 as target
miravirsen
Second Generation HCV Protease
Inhibitor: Simeprevir (Olysio) Indicated for chronic hepatitis C in combination with
peg-interferon and ribavirin.
Potent against genotypes 1,4,6; activity against 2,5
Dose: 150 mg once daily with food
Renal adjustment: none, but not tested in CrCl <30 mL/min
Contains sulfonamide moiety; caution in patients with sulfa
allergy?
SE: elevated bilirubin, photosensitivity, rash, pruritus, nausea
Safe and well-tolerated
Resistance possible with Q80K mutation within protease
Drug interactions: CYP3A, Pgp,OATP 1B1/3
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HCV Polymerase Inhibitor:
Sofosbuvir (Sovaldi) indicated for treatment of chronic hepatitis C
infection as part of a combination antiviral regimen
Potent against all genotypes
Dose: 400 mg once daily with or without food
Renal adjustment: none, but not tested in CrCl <30
mL/min
Safe and well-tolerated
SE: most ADRs in clinical trails attributed to other agents;
most common: fatigue, headache, nausea, insomnia, and
anemia
High barrier to resistance (no known breakthroughs if
adherent to therapy)
Drug interactions: Pgp inducers
October 2, 2014 20
Summary of Major Differences
10/2/2014 21
10/2/2014 22
Sofosbuvir + PEG-Interferon/ Ribavirin for
Genotype 1,4,5,6 infections: NEUTRINO
trial
10/2/2014 23
Lawitz E et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013b;368(20):1878-
1887.
10/2/2014 24
Simeprevir +PEG-interferon/ Ribavirin:
QUEST trials
10/2/2014 25
Jacobson IM et al. Simeprevir (TMC435) with Peginterferon/ Ribavirin for Chronic HCV Genotype-1 Infection in
Treatment-Naive Patients: Results From QUEST-1, a Phase III Trial. Digestive Disease Week. May 18-21, 2013;
Orlando, FL.
Poordad F et al. Simeprevir (TMC435) with Peginterferon/Ribavirin for Treatment of Chronic HCV Genotype-1 Infection
in Treatment-Naive Patients: Results From QUEST-2, a Phase III Trial. Digestive Disease Week. May 18-21, 2013,
2013; Orlando, FL.
10/2/2014 26
COSMOS Response by HCV Subtype
and Q80K Mutation
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Jacobson IM, Ghalib R, Rodriguez-Tirres M, et al. SVR results of a once-daily regimen of simeprevir plus sofosbuvir
with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naive and prior null responder
patients: The COSMOS study. Presented at the 64th annual meeting of the American Association for the Study of
Liver Diseases, Washington, DC, November 1-5, 2013
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PHOTON Trial: Virologic Response
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Sulkowski M et al. All-Oral Therapy with Sofosbuvir Plus Ribavirin for the treatment of HCV genotype 1,2 and 3
infection in patients coinfected with HIV (PHOTON-1). AASLD Annual Meeting 2013. Nov 1-5, 2013, 2013c;
Washington, DC.
PHOTON Trial: Virologic Response
10/2/2014 30
Sulkowski M et al. All-Oral Therapy with Sofosbuvir Plus Ribavirin for the treatment of HCV genotype 1,2 and 3
infection in patients coinfected with HIV (PHOTON-1). AASLD Annual Meeting 2013. Nov 1-5, 2013, 2013c;
Washington, DC.
Pipeline Agents:
Daclatasvir + Sofosbuvir +/- Ribavirin for
1st Generation Protease Inhibitor Failure
10/2/2014 31
Sulkowski MS et al. Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection. N Engl
J Med 2014; 370:211-221.
Pipeline Agents:
Interferon-Free Regimens in Phase 3 for
Genotype 1
10/2/2014 32
Feld JJ et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med.
2014;370(17):1594-1603.
Zeuzem S. et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med.
2014;370(17):1604-14.
Afdhal N et al. Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection N Engl J Med. 2014;370(20):1889-98.
Kowdley KV, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;
370 (20):1879-88.
Afdhal N et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med.
2014;370(16):1483-93.
Pipeline Agents:
AbbVie’s All Oral Three Drug Regimen
for Genotype 1 Infection
10/2/2014 33
AbbVie website. http://abbvie.mediaroom.com/2014-04-22-AbbVie-Submits-New-Drug-Application-to-U-S-FDA-for-its-
Investigational-All-Oral-Interferon-Free-Therapy-for-the-Treatment-of-Hepatitis-C. Accessed May 15, 2014.
Pipeline Agents:
SYNERGY Trial: High Rates of SVR
With Just Six Weeks of Therapy!
10/2/2014 34
A Kohli et al. Combination Oral Hepatitis C Antiviral Therapy for 6 or 12 Weeks: Final Results of the SYNERGY Trial.
21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 27LB.
Cost of These Newer Therapies
Sofosbuvir (Sovaldi) is $1000/pill for 12 weeks= $84,000
Simeprevir (Olysio) for 12 weeks = $65,000.
For treatment-naïve patients eligible to receive interferon
> Recommended: Sofosbuvir + peg-interferon/ ribavirin for 12
weeks = $90,000
> Alternative: Simeprevir for 12 weeks + peg-interferon/ ribavirin
for 24 weeks= $78,000.
For treatment-naïve patients NOT eligible to receive
interferon
> Recommended (off label): Twelve weeks of sofosbuvir +
simeprevir +/- ribavirin costs about $149,000.
> Alternative: Twenty-four weeks of sofosbuvir + ribavirin costs
about $168,000.
10/2/2014 35
Best Options for Genotype 1 HCV
Infection (for now) For treatment-naïve patients eligible to receive interferon
Recommended: Sofosbuvir + peg-interferon/ ribavirin for
12 weeks
> The Good:
~90% cure rate in the NEUTRINO study
Only 12 weeks of interferon and ribavirin
> The Bad:
Ribavirin and all its side effects.
Interferon and all its side effects.
> The Ugly:
Cost = $90,000
10/2/2014 36
Best Options for Genotype 1 HCV
Infection (for now)
For treatment-naïve patients eligible to receive interferon
Alternative: Simeprevir for 12 weeks + peg-interferon/
ribavirin for 24 weeks
> The Good:
80% cure rate in the QUEST studies
> The Bad:
Simeprevir can lead to photosensitivity and has many drug-drug
interactions.
The Q80K polymorphism may reduce response to simeprevir.
Ribavirin and all its side effects.
Interferon and all its side effects.
> The Ugly:
Cost = $78,000
10/2/2014 37
Best Options for Genotype 1 HCV
Infection (for now)
For treatment-naïve patients NOT eligible to receive
interferon
Recommended: Simeprevir + sofosbuvir +/- ribavirin for
12 weeks
> The Good:
Cure rates of 89-100% in the COSMOS study
Two pills once daily AND ribavirin does not appear to be necessary
> The Bad:
The COSMOS study was very small.
Simeprevir can lead to photosensitivity and has many drug-drug
interactions.
The Q80K polymorphism may reduce response to simeprevir.
This regimen is not “FDA approved.”
> The Ugly:
Cost = $149,000
10/2/2014 38
Best Options for Genotype 1 HCV
Infection (for now)
For treatment-naïve patients NOT eligible to receive
interferon
Alternative: Sofosbuvir + ribavirin for 24 weeks
> The Good:
Cured 76% of HIV/HCV co-infected patients in the PHOTON-1 study
(may do better in HCV mono-infected)
Regimen is “FDA approved” for interferon-ineligible patients, which
could help get insurance coverage.
> The Bad:
Ribavirin and all its side effects.
24 weeks compared to 12 weeks
SVR is lower than other potential therapies, which could require re-
treatment.
> The Ugly:
Cost (not including ribavirin) = $168,000
10/2/2014 39
To Treat or To Defer Therapy?
Patients with mild disease
> Possibly defer therapy to wait for non-interferon regimens
(probably out by end of 2014)
Patients with advanced fibrosis but no cirrhosis
> Some risk of decompensation: patients given option of waiting or
starting therapy (NEUTRINO regimen)
Patients with cirrhosis
> All patients offered therapy!
> COSMOS regimen: for GT1b no ribavirin, for people with GT1a,
add ribavirin due to Q80K polymorphism
10/2/2014 40
Ideal Regimen for HCV
high potency
little resistance
tolerable
once daily
shorter duration
few drug interactions
lower cost
10/2/2014 41
Role of the Pharmacist
Drug information
Screening for drug interactions/side effects
Insurance benefit investigation
Stressing necessity of adherence
Patient/physician education
10/2/2014 42
Acknowledgments
Some presentation materials adapted from the following
sources/websites:
> Dr. Arthur Kim, Massachusetts General Hospital
> hcvguidelines.org
> www.cdc.gov/Hepatitis/C/index.htm
> http://hepatitiscnewdrugresearch.com/index.html
10/2/2014 43
Thank you!
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