This document discusses hepatitis C virus (HCV) and current treatment options. It provides the following key points: - HCV is the most common blood-borne pathogen in the US, with around 3.2 million people chronically infected. Chronic infections often progress to cirrhosis over 20-30 years. - New all-oral treatment regimens that do not require interferon are highly effective. Sofosbuvir-based combinations can achieve over 90% sustained virologic response rates. - Treatment is now recommended for most patients with chronic HCV to prevent long-term complications like cirrhosis and liver cancer. However, costs remain very high, with prices over $80,000 for a

1. Jenny Chan 10/16/14
PharmD Candidate c/o 2015
Providence Everett Ambulatory Care
Image from: http://www.emcdda.europa.eu/userfiles/image/pods/hcv/hcvVirus380x285.jp1

2. • Most common blood-borne pathogen.
• In the U.S. approx. 3.2 million people chronically
infected.
• Nearly 85% of acutely infected patients go on to
develop chronic infections.
• Chronic infections will eventually progress to
cirrhosis in 20-30 years.
• Characteristics of HCV
• Single stranded RNA virus without a proofreading
polymerase
• Fast viral replication (est. serum half-life 2-3 hours)
2

3. • 6 major genotypes (1-6, subdivided into a and b)
• Most common genotype: 1a/1b followed by genotypes
2 and 3.
• Genotypes 4, 5, 6 more uncommon.
• Genotype determines treatment success.
• Genotype 1 is more difficult to treat.
• High risk groups
• Injection drug users
• Prisoners
• Homeless people
3

4. • Currently, HCV is not
vaccine preventable.
• The high mutation rate
and variable surface make
vaccine development a
challenge.
• However, Inovio is
currently developing a
synthetic multi-antigen
DNA immunotherapy
targeting HCV genotypes
1a and 1b and antigens
NS3/4A. INO-800 HCV is
in Phase I clinical trials
and results expected in
2015.INO-8000 HCV. http://www.inovio.com/products/infectious-disease-vaccines/hepatitis/ino8000HCV/
Study protocol: http://clinicaltrials.gov/show/NCT02027116
Image: http://www.inovio.com/technology/electroporation-delivery/electroporation-devices/intramuscular-delivery/4

5. Interferon Eligible
• Daily sofosbuvir (400 mg)
and weight-based RBV
(1000 mg [<75 kg] to 1200
mg [>75 kg]) plus weekly
PEG for 12 weeks is
recommended for IFN-
eligible persons with HCV
genotype 1 infection,
regardless of subtype.
Not Eligible for Interferon
• Daily sofosbuvir (400 mg)
plus simeprevir (150 mg),
with or without weight-
based RBV (1000 mg
[<75 kg] to 1200 mg [>75
kg] for 12 weeks is
recommended
• RBV: ribavirin
5

6. • Intolerance to IFN
• Autoimmune hepatitis or other autoimmune disorders
• Hypersensitivity to PEG or any of its components
• Decompensated hepatic disease
• Major uncontrolled depressive illness
• A baseline neutrophil count below 1500/uL, a baseline
platelet count below 90,000/uL or baseline hemoglobin
below 10 g/dL
• A history of preexisting cardiac disease
6

7. No Previous HCV PI
• Daily sofosbuvir (400 mg)
plus simeprevir (150 mg),
with or without weight-
based RBV (1000 mg
[<75 kg] to 1200 mg [>75
kg]) for 12 weeks is
recommended for
retreatment of HCV
genotype 1 infection,
regardless of subtype or
IFN eligibility.
Previous HCV PI
• Daily sofosbuvir (400 mg)
for 12 weeks plus weight-
based RBV (1000 mg
[<75 kg] to 1200 mg [>75
kg]) and weekly PEG for
12 to 24 weeks is
recommended for
retreatment of HCV
genotype 1 infection,
regardless of subtype
7

8. Treatment Naïve
• Daily sofosbuvir (400 mg)
and weight-based RBV
(1000 mg [<75 kg] to 1200
mg [>75 kg]) for 12 weeks
is recommended for
treatment-naive patients
with HCV genotype 2
infection.
Treatment Experienced
• Daily sofosbuvir (400 mg)
for 12 weeks and weight-
based RBV (1000 mg
[<75 kg] to 1200 mg [>75
kg]) plus weekly PEG for
12 to 24 weeks is an
alternative for retreatment
of IFN-eligible persons
with HCV genotype 1
infection, regardless of
subtype.
8

9. • Treatment is recommended for patients with chronic HCV
infection and highest priority given to those patients with
advanced fibrosis, compensated cirrhosis, liver transplant
patients and patients with severe extrahepatic disease.
• Treatment not recommended for the following:
• Patients with limited life expectancy (<12 months) due to non-liver
issues
• Patients in whom HCV therapy would not improve symptoms or
prognosis
• Cost of treatment
• Solvaldi (sofosbuvir): $1000/pill, or $84,000 for a typical 12 week
course plus cost of other medications
• Harvoni (sofosbuvir/ledipasvir): $1125/pill, or $94,500 for a 12-
week course. Approved 10/10/14 for standalone use.
Harvoni, a Hepatitis C Drug From Gilead, Wins F.D.A. Approval. Oct 10, 2014.
http://www.nytimes.com/2014/10/11/business/harvoni-a-hepatitis-c-drug-from-gilead-wins-fda-approval.html9

10. Study Design Genotype SVR4 SVR12
FISSION SOF 400 mg/RBV 12 wk (n =
253) OR PEG/RBV (n = 243)
2, 3; naïve 74 67 (G2 97; G3 56)67
NEUTRINO SOF 400 mg/RBV/PEG 12 wk
(n = 327)
1, 4, 5, 6; naïve (98% G1 or 4) 92 90 (G1a 92; G1b 82;
G4 96)
POSITRON SOF 400 mg/RBV (n = 207) OR
Placebo (n = 71) 12 weeks
2, 3; naïve (IFN not an option) 83 78 (G2 93; G3 61)
FUSION SOF 400 mg/RBV 2, 3; previous treatment failure
12 weeks (n=103) OR 56 50 (G2 86; G3 30)
16 weeks (n = 98) 77 73 (G2 94; G3 62)
Figure modified from Table 2: Phase III studies of sofosbuvir.
Stedman C. Sofosbuvir, a NS5B polymerase inhibitor in the treatment of hepatitis C: a review
of its clinical potential. Therap Adv Gastroenterol. May 2014; 7(3): 131-40. doi:
10.1177/1756283X1515825. 10
Sustained Virologic Response (SVR): defined as serum HCV below 25
copies/mL 12 weeks after treatment cessation.

11. • ~30-40% of HIV infected people are coinfected with HCV
and this proportion is even higher in IVDU
• HIV infection results in more rapid progression to liver
cirrhosis, ESLD, and hepatocellular carcinoma but the
effects of HCV infection on HIV are unclear.
• Multivariate Cox-regression model used on ERCHIVES
• Among 8,039 HIV infected US veterans, 65% had HCV
coinfection.
• All-cause mortality rate 74.1 per 1000 person-years (PY) with
HIV/HCV coinfection compared to 39.8 per PY with HIV
monoinfection.
• HCV treatment, higher CD4 count, and higher BMI are predictors
of decreased mortality.Erqou S, Mohanty A, Murtaza Kasi P, Butt A. Predictors of Mortality among United States Veterans with Human
Immunodeficiency Virus and Hepatitis C Virus Coinfection. ISRN Gastroenterol [Internet]. 2014 April 7 [cited 2014
DOI: 10.1155/2014/764540 11

12. • TURQUOISE-1
• Randomized open-label trial
• Hep C genotype 1 patients with well-controlled HIV on
antiretroviral regimens that included raltegravir or PI
atazanavir.
• Duration:12 and 24 weeks
• Triple Regimen
• ABT-450 (ritonavir/ombitasvir)
• Dasabuvir
• Weight-based RBV
• Results
• 12-week tx group: SVR 12 weeks after tx cessation was 93.5%
• 24-week tx group: SVR 4 weeks after tx cessation was 97%Oral Hepatitis C Drugs Helping Patients Coinfected with HIV. July 25,2014.
http://www.medscape.com/viewarticle/828945#vp_1.
12

13. • PHOTON-2
• Open-label nonrandomized and uncontrolled trial
• Hep C genotype 1-4 patients on a backbone HIV regimen
that consisted of tenofovir plus emtricitabine
• Regimen
• Sofosbuvir 400 mg a day plus weight-based RBV
• Duration:
• Treatment naïve GT 1, 3, 4: 24 weeks
• Treatment naïve GT 2: 12 weeks
• Treatment experienced GT 2,3: 24 weeks
• Results
• Over 80% SVR at 12 weeks after tx cessation in all genotypes
Oral Hepatitis C Drugs Helping Patients Coinfected with HIV. July 25,2014.
http://www.medscape.com/viewarticle/828945#vp_1. 13

14. • HCV prevalence in pregnant women is low (1-2%) in
most western countries but much higher in developing
countries.
• Acute infection during pregnancy is rare. Most common
scenario is chronic infection.
• Risks of HCV infection
• Premature rupture of membrane and caesarean delivery
• Increased risk of gestational diabetes in mothers with excessive
weight gain.
• May exacerbate chronic hepatitis and worsen liver function in
women with liver cirrhosis
• Vertical transmission
• Mother-to-child HCV transmission rate is low (3-5%).
• Transmission rate increases up to 19.4% if the mother is HIV(+).
14

15. • Should pregnant women be treated?
• Which drug is NOT recommended for use in pregnant
women or women who may become pregnant?
• For how long should pregnancy be avoided after using
one of the agents above?
• Other options?
15

16. • Spontaneous clearance of HCV has been reported in up
to 25-30% of HCV-infected children.
• Children 2 years or older are eligible for treatment but not
all children should be treated.
• Treat only those at high risk of progression?
• Pediatric HCV infection is associated with minimal or mild
liver disease. Hepatocellular carcinoma is rare in children
with HCV infection.
Tosone G, Enrico Maraolo A, Mascolo S, Palmiero G, Tambaro O, Orlando R. Vertical hepatitis C vir
transmission: Main questions and answers. World J Hepat [Internet]. 2014 Aug 27 [cited 2014 Oct 1
6(8): 538-48. doi: 10.4254/wjh.v6.i8.538 16

17. • Statins may provide additional benefit to treatment of HCV.
• Phase 2 Randomized controlled trial (n=45)
• Fluvastatin or simvastatin has some antiviral activity against
HCV as monotherapy.
• The addition of fluvastatin or simvastatin to PEG-IFN/RBV
for 48 weeks in HCV genotype 1 treatment-naïve patients
showed a trend towards improving SVR (not statistically
significant).
• 13 patients (statin) vs 5 patients (placebo) achieved SVR
• Statin therapy was well-tolerated. No reports of unusual
muscle pain.
17
Bader T, Hughes LD, Fazili J, Frost B, Dunnam M, Gonterman A, Madhoun M, Aston CE. A randomized controlled
Adding fluvastatin to peginterferon and ribavirin for naïve genotype 1 hepatitis C patients. J Viral Hept [Internet].
2013 Mar 6 [cited 2014 Oct 15]. 20)9):622-7. DOI: 10.1111/jvh.12085.

18. • Statins may have a protective effect on hepatocellular
carcinoma (HCC) in HCV patients.
• Population-based cohort study (n= 260,864)
• HCV patients enrolled in a Taiwanese database from 1999-
2010
• Statin used defined as >28 cumulative daily doses.
• 13.4% of this population used statins
• 10.7% of this population were diagnosed with HCC
• Adjusted HR 0.53; 95% CI, 0.49 to 0.58) after controlling for
confounders (age, sex, urbanization, income, liver cirrhosis,
and diabetes)
18
Tsan Y, Lee C Ho W, Lin M, Wang J, Chen P. Statins and the Risk of Hepatocellular Carcinoma in P
With Hepatitis C Virus Infection. JCO [Internet] 2013 Mar 18 [cited 2014 Oct 15]. 31(12): 1514-21.
DOI: 10.1200/JCO.2012.44.6831.

19. 19
Statin PI Magnitude of
interaction (fold)
Recommendation
Lovastatin,
Simvastatin
All Up to 30 Should not be co-
administered
Atorvastatin Teleprevir 8 Should not be co-
administered
Pitavastatin All 0.7-1 Start at standard dose
Pravastatin All 0.7-1 Start at standard dose
Rosuvastatin All 1-3 Avoid if possible. Start at 5
mg. Max daily dose= 10 mg
Fluvastatin All No data Coadministration probably
safe. Start at standard dose.All = All ritonavir- or cobicistat-boosted HIV + PIs or other ARV and boceprevir and telaprevir.
Chauvin B, Drouot S, Barrail-Tran A, Taburet A. Drug-Drug Interactions Between HMG-CoA Reductase Inhibitors
(Statins) and Antiviral Protease Inhibitors. Clin PHarmacokinet [Internet]. 2013 May 24 [cited 2014 Oct 15].
52:815-31. DOI: 10.1007/s40262-013-0075-4

20. Phase 2
Drug Category Drug Name
Protease
Inhibitors
ACH-2684
Danoprevir
Sovaprevir
NS5A Inhibitors ACH-3102
NS5A Inhibitor/PI Daclatasvir/Simeprevir
IDX719/Simeprevir
ACH-3102/Sovaprevir
NS5A Inhibitor/
Polymerase
Inhibitor
GS-5816/Sofosbuvir
PI/Polymerase
Inh.
Simeprevir/TMC64705
5/Ritonavir
Phase 3
Drug Category Drug Name
PI/NS5A Inh/Poly
Inh
ABT-450/r,
Ombitasvir/Dasabuvir
NS5A Inhibitor/PI/
Polymerase
Inhibitor
Daclatasvir/
Asunaprevir/
BMS-791325
PI/NS5A inhibitor MK-5172/MK-8742
NS5A Inh./Poly
Inh.
Daclatasvir/Sofosbuvi
r
Hepatitis C Treatments in Current Clinical Development. Updated Sept 17, 2014.
http://hcvadvocate.org/hepatitis/hepc/Quick_Ref_Guide.pdf
Red: Submitted to the FDA.
Expected approval Dec 2014
20

21. Phase 2
Drug Name Drug Category
Resminostat HDAC Inhibitor
CF102 A3AR
Agonist/Anti-Liver
Cancer
GI-5005 Therapeutic
Vaccine
Miravirsen microRNA
Oral Interferon Oral Interferon
SCY-635 Cyclophilin
Inhibitor
TG4040 Therapeutic
Vaccine
Phase 3
Drug Name Drug Category
Alinia Thiazolides
Doxorubicin Anti-Liver Cancer
Livatag
(Doxorubicin/Transdru
g)
Anti-Liver Cancer
Hepatitis C Treatments in Current Clinical Development. Updated Sept 17, 2014.
http://hcvadvocate.org/hepatitis/hepc/Quick_Ref_Guide.pdf 21

22. • Deming P. Chapter 26. Viral Hepatitis. In: DiPiro JT, Talbert RL, Yee GC,
Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic
Approach, 9e. New York, NY: McGraw-Hill; 2014.
http://accesspharmacy.mhmedical.com.offcampus.lib.washington.edu/conten
t.aspx?bookid=689&Sectionid=48811468. Accessed October 11, 2014.
• AASLD/IDSA/IAS–USA. Recommendations for Testing, Managing and
Treating Hepatitis C. Updated Aug 11, 2014. Available from:
http://www.hcvguidelines.org. Accessed Oct 8, 2014.
22