Teresa M. Cavanaugh, PharmD, MS, BCPS
Assistant Professor of Pharmacy Practice,
James L. Winkle College of Pharmacy,
University of Cincinnati
Transplant Pharmacist, Liver Transplant Clinic,
University of Cincinnati Medical Center
Objectives
Pharmacist Objectives: Compare and contrast newly approved hepatitis
C direct-acting agents including telaprevir, boceprevir, simeprevir and sofosbuvir
Describe appropriate response-guided hepatitis C therapy based upon viral detectability in the blood
Explain the management of drug interactions and side effects of hepatitis C therapy
Pharmacy Technician Objective List the drug therapies of the hepatitis C direct-
acting medications
Hepatitis C Virus (HCV)
Infection
Most common blood-borne infection 170 million cases worldwide and 3.5 million in the US
40% of chronic liver disease
8,000-10,000 HCV related deaths per year in the US
NHANES study from 1988-1994
○ 3.9 million persons in the US (1.8% of the population)
were infected
○ 2.7 million of these had chronic infection
○ Homeless, incarcerated?
A 4-fold increase in the number of adults diagnosed with
HCV projected between 1990-2015
Mortality
By 2007, HCV surpassed HIV as a cause of death in the US
Ly KN, et al. Ann Intern Med 2012;156:271-278.
Annual age-adjusted mortality rates from hepatitis B and hepatitis C
virus and HIV infections listed as causes of death in the United States
between 1999 and 2007.
Transmission
Hepatitis GT
Enveloped, spherical, single-stranded RNA flavivirus No DNA integration
6 well-known GT and 50 subtypes Common in the US
○ GT1
GT1b is the most aggressive and resistant form
○ GT2 and GT3 historically more responsive to therapy and require shorter duration of therapy
GT4 common in Egypt and Africa
GT5 common in South Africa
GT6 common in Southeast Asia
Disease Progression
Hoofnagle JH. Hepatology 2002;36:S21-
S29.
Clinical Presentation
Acute Asymptomatic
Symptomatic (25% of patients) ○ Malaise, anorexia, jaundice
○ Can be severe, but fulminant disease is rare
LFTs elevated within 4-12 weeks of exposure
Chronic Asymptomatic until the development of progressive liver fibrosis
Mild but persistently elevated LFTs
Symptoms: ○ Non-specific: Fatigue, malaise, anorexia, weight loss, hepatomegaly
○ Extra-hepatic: renal disease (nephrotic syndrome), peripheral neuropathy, lymphoma, Sjögren’s syndrome
10-30% develop cirrhosis
1-5% develop hepatocellular carcinoma
Goals of Therapy
Return the patient to the previous state of health and prevent development of chronic infection
Stop viral replication and ultimately eradicate the virus [Sustained virological response (SVR)]
Decrease morbidity and mortality “For patients with chronic HCV infection, achieving an
undetectable viral load reduces the risk for death by 45% and the risk for liver-related adverse events by 27%.”
Minimize spread of infection
http://www.scribd.com/fullscreen/210352863?access_key=key-1bjl16y2nilwusx1aijf&allow_share=false&escape=false&show_recommendations=false&view_mode=slideshow
Response Terminology
http://www.hepatitis.va.gov/provider/guidelines/2012HCV-definitions-of-response.asp
Predictors of SVR in GT1
HCV Patient population 1,604 from the IDEAL
trial and 67 patients from other studies rs12979860cc GT: OR 5.2 (CI 4.1-6.7)
HCV RNA <600,000 IU/mL: OR 3.1 (CI 2.3-4.1)
White vs black: OR 2.8 (CI 2.0-4.0)
Hispanic vs black: OR 2.1 (CI 1.3-3.6)
Lower level of fibrosis on biopsy: OR 2.7 (CI 1.8-4.0)
Fasting blood sugar < 100 mg/dL: OR 1.7 (CI 1.3-2.2)
Thompson AJ, et al. Gastroenterology. 2010;139-120-129.
Early Acute Treatment
Symptomatic acute HCV Standard interferon or pegylated interferon monotherapy for 24
weeks can prevent development of chronic HCV approximately 90% of the time ○ Combination with ribavirin is not necessary
Symptomatic patients may clear HCV spontaneously within the first 12 weeks ○ 15-25% of exposed individuals will clear the virus without therapy
Post-exposure prophylaxis (needle stick) Unnecessary
○ Infection needs to occur for interferon to have an effect
○ No evidence to suggest this is effective
○ Low rate of transmission from occupational needle stick
Early identification and treatment, if appropriate, of chronic disease
Evolution of HCV Therapy
1997
• Interferon alfacon-1 (Infergen®)
• Interferon alfa 2b (Intron-A®)
1999 • Interferon alfa 2a (Roferon-A®)
2001 • Interferon alfa 2b (PEG-Intron®)
2002 • Pegylated Interferon alfa 2a (Pegasys®)
2011
• Boceprevir (Victrelis®)
• Telaprevir (Incivek®)
2013
• Simeprevir (Olysio®)
• Sofosbuvir (Sovaldi®)
Interferon
Formulations Effects
Interferon Formulations Non-pegylated
○ Interferon alfa 2a (Roferon-
A®) ○ Interferon alfa 2b (Intron-
A®) ○ Interferon alfacon-1
(Infergen®)
Pegylated
○ Peg-Interferon alfa 2b (Pegasys®)
○ Peg-Interferon alfacon-1 (Infergen ®)
Direct antiviral actions Inhibits viral entry and
uncoating
Inhibits viral RNA synthesis
Inhibits viral protein synthesis
Indirect antiviral effects Induces immune response
Other effects Antiproliferation
Antifibrosis
Ribavirin
Ribavirin A guanosine nucleotide analog that inhibits viral
replication and works synergistically with interferon alfa
Direct antiviral actions
Increase the mutation frequency in the genomes of
several RNA viruses
Inhibits viral hepatitis C polymerase activity
Dose and Duration
Side Effects
10-40% of patients
require a dose
reduction
10-14% of patients
discontinue
treatment due to
adverse event
Interferon Serious Side Effects
Bone marrow depression Thrombocytopenia
○ Sargramostim (Leukine®): granulocyte macrophage colony stimulating factor
Leukopenia ○ Filgrastim (Neupogen®): colony stimulating factor
Neuropsychiatric symptoms May affect family members
Severe depression and suicide have been reported ○ Selective serotonin reuptake inhibitors
○ Psych referral
○ Avoid stimulants
○ Consider short acting benzodiazepines
Ribavirin Serious Side
Effects Hemolytic anemia
Occurs within the first 1-2 weeks and hemoglobin remains
low
Anemia during the first 4-8 weeks is associated with an
improved probability of achieving RVR/SVR
Patient experiences significant fatigue, shortness of
breath, cardiovascular effects and decreased quality of life
Can result in dose reduction/discontinuation which may
affect SVR
○ Erythropoietin stimulating agents
Epoetin alfa (Epogen®, Procrit®)
Darbepoetin alfa (Aranesp®)
Managing Bone Marrow
Suppression
Laboratory Parameter Recommendations
If Hgb < 10 to ≥ 8.5 g/dL Reduce dose by 200 mg/wk to no
lower than 600 mg/day total dose
Consider ESA with target Hgb of
≤11 mg/dL
If Hgb ≤ 8.5 mg/dL Discontinue ribavirin
If ANC < 750 Reduce PegIFN 2a to 135 mcg/wk or
PegIFN 2b to 1 mcg/kg/wk
If ANC < 500 Discontinue therapy
If platelets < 50,000 Reduce PegIFN 2a to 90 mcg/wk or
PegIFN 2b to 1 mcg/kg/wk
If platelets < 25,000 Discontinue therapy
Contraindications
Interferon
Contraindications Decompensated cirrhosis Leukopenia
Thrombocytopenia Uncontrolled thyroid disorder
Uncontrolled psychiatric illness Untreated autoimmune diseases
Ribavirin Contraindications Hemoglobinopathies Pregnancy (teratogen!)
Hgb <12 g/dL in women, <13 g/dL in men
Common Side Effects of Combination
Pegylated Interferon & Ribavirin
Headache (47-62%)
Pyrexia (40-46%)
Myalgia (37-56%)
Rigors (24-48%)
Arthralgias (24-34%)
Nausea (35-43%)
Loss of Appetite (21%)
Weight loss (29%)
Irritability (24-35%)
Depression (22-31%)
Diarrhea (22%)
Alopecia (21-36%)
Rash/dermatitis (20-24%)
Injection site inflammation (25%)
Pruritus (25-29%)
Dyspnea (26%)
Fatigue (48-64%)
Insomnia (33-40%)
Managing Common Side
Effects Flu-like symptoms
APAP (≤ 2 g/day)
Bed rest
Fluids
Fatigue
Nighttime interferon
administration
Low impact exercise
Short naps and adjusted work
schedule
Insomnia
Good sleep hygiene
Consider medications
(diphenhydramine, trazodone,
zolpidem)
Nausea, anorexia
Take ribavirin with food
Eat 6-8 small meals per day
Ginger – tea, ale, syrup
Carbonated fluids
Jell-O
Prophylactic antiemetics
(prochlorperazine)
Managing Common Side
Effects Diarrhea
Non-caffeinated fluids
(Gatorade)
Increase fiber (BRAT
diet)
Avoid spicy, greasy or
acidic foods
Consider anti-diarrheals
(loperamide) or psyllium
Skin Irritation
Rotate injection sites
Take cool baths
Moisturizing soaps
Oral antihistamines
Hair loss/thinning
Wigs
Education
Sustained Viral Response
Rates
Direct Acting Agents: A New Era
for Treating HCV
Hepatitis C Virus
C E1 E2 NS
2 NS3 NS4B NS5A NS5B
5’UTR 3’UT
R
Forms viral
capsid
Components
of HCV virion
envelope
Necessary for
viral entry and
fusion
C: Core
E: Envelope
NS: Nonstructural
UTR:
Untranslated
Contains 2
internal signal
sequences that
are responsible
for ER
membrane
association
NS4A
NS4A is a
cofactor for
NS3 protease
Essential for
HCV lifecycle
Membrane
anchor for
replication
Virus replication
and regulation
of cellular
pathways
NS5B RNA-Dependent
RNA Polymerase
“fingers, palm, and
thumb” structure
Synthesis of positive- and
negative-strand HCV
RNAs
Chevaliez S, Pawlotsky JM. HCV Genome and Life Cycle. In: Tan SL, editor. Hepatitis C Viruses: Genomes and Molecular Biology. Norfolk (UK): Horizon
Bioscience; 2006. Chapter 1. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1630/
IRES region
Controls HCV
genome
translation
RNA
elements
for viral
replication
and
translation
The Sad Story of the HCV
Protease Inhibitors
Protease Inhibitors
Telaprevir (Incivek®)
NS3/4A protease inhibitor
Boceprevir (Victrelis®)
Competitive inhibitor of NS3 protease
complex of HCV GT1
Given in combination with PegIFN
and RBV
Telaprevir
Prove 1 263 patients, treatment naive,
genotype 1
SVR ranged from 61-67%
Prove 2 334 patients, treatment naive,
genotype 1
SVR ranged from 60-69%
Prove 3 453 patients, genotype 1 non-
responders or relapsers to prior standard therapy
SVR ranged from 24-53%
ADVANCE 1088 treatment naïve patients
with genotype 1
SVR ranged from 57-58%
REALIZE 662 patients, previously failed
standard therapy
SVR ranged from 31-57%
Illuminate 540 patients, genotype 1,
treatment naïve
SVR ranged from 72%
Extend 99% of patients who had
achieved SVR have maintained SVR
Telaprevir
Total therapy duration either 24 or 48 weeks
Triple therapy for 12 weeks followed by dual therapy
Dose is 750 mg (2 x 375 mg) q8h within 30 min of 20 gm fat-containing meal
TEL/PegIFN/RBV
12 weeks
PegIFN/RBV
12 or 36
weeks
Telaprevir Length of
Therapy Total 24 weeks of therapy for:
Treatment naïve
Treatment experienced relapsers with no cirrhosis
Total 48 weeks of therapy for:
Treatment naïve with cirrhosis
Treatment experienced but only partial or null
responders
Telaprevir Response-Guided
Therapy Week 4
Undetectable (eRVR) ○ Great indicator for SVR
○ Continue therapy
Detectable but less HCV RNA < 1000 IU/mL ○ Continue TEL/PegIFN/RBV
therapy to week 12
Detectable and HCV RNA > 1000 ○ Discontinue therapy
Week 12 ○ Undetectable
Continue therapy
○ Detectable but less HCV RNA < 1000 IU/mL Continue therapy
PegIFN/RBV to either week 24 or 48
○ Detectable and HCV RNA > 1000 Discontinue therapy
Week 24: If HCV RNA is at all detectable, STOP therapy
Boceprevir
HCV Sprint-1
595 patients genotype 1,
treatment naïve
SVR 56-75%
HCV Sprint-2
1097 patients, genotype 1,
treatment naïve
Non-black SVR 40-68%
Black SVR 23-53%
RESPOND-2
403 patients, partial
responders or relapsers
Partial responder SVR 7-52%
Relapsers 29-75%
Boceprevir
1. MUST HAVE A 4-WEEK PegIFN/RBV
LEAD-IN!
2. Dose is 800 mg (4 x 200 mg tablets)
q8h with a light meal or snack
Assessment
(HCV-RNA Results)
Recommendation
At Treatment
Week 8
At Treatment
Week 24
(All patients have a 4 week PegIFN/RBV lead-in)
Previously
Untreated Patients
Undetectable Undetectable Complete triple therapy by week 28
(4 weeks PegIFN/RBV lead-in and 24 weeks triple therapy)
Detectable Undetectable 1. Continue triple therapy through week 36 and then
2. Continue with PegIFN/RBV through week 48
(4 weeks PegIFN/RBV lead-in and 32 weeks triple therapy
followed then 12 weeks of PegIFN/RBV)
Previously Partial
Responders or
Relapsers
Undetectable Undetectable Complete triple therapy by week 36
(4 weeks PegIFN/RBV lead-in and 32 weeks triple therapy)
Detectable Undetectable 1. Continue triple therapy through week 36 and then
2. Continue with PegIFN/RBV through week 48
(4 weeks PegIFN/RBV lead-in and 32 weeks triple therapy
followed then 12 weeks of PegIFN/RBV)
Boceprevir Response Guided
Therapy
Considerations of First
Generation Protease Inhibitors
Boceprevir has no activity against non-GT1
genotypes
Monotherapy with a protease inhibitor
leads to rapid resistance, thus combination
therapy required
Black patients respond less well to antiviral
therapy
The presence of cirrhosis has a negative
impact on response to therapy
Side Effects
Boceprevir Telaprevir
Fatigue
Anemia
Neutropenia
Thrombocytopenia
GI upset
Headaches
Dysgeusia
Rash - Mild to Steven’s Johnson
Fatigue
Anemia
Increased uric acid
Anorectal issues
Increased bilirubin
STILL TAKING PegIFN AND
RBV!!!!!
Drug-Drug Interactions
Telaprevir Inhibitor and substrate of both CYP 3A4 and P-
gp
Contraindicated ○ Drugs that are highly dependent on 3A4
metabolism for clearance
○ Drugs that strongly induce 3A4
Boceprevir Strong inhibitor of CYP 3A/5
Contraindicated ○ Drugs that are highly dependent on 3A4/5
metabolism for clearance
○ Drugs that strongly induce 3A4/5
Sofosbuvir (Sovaldi®)
A nucleotide analog NS5B polymerase inhibitor
Acts as an HCV RNA chain terminator
Indicated for the treatment of chronic HCV
infection as a component of a combination
antiviral treatment regimen
HCV Mono-
infected and
HCV/HIV Infected
Treatment Duration
GT1 or 4 Sofosbuvir +
PegIFN + RBV
12 weeks
GT2 Sofosbuvir + RBV 12 weeks
GT3 Sofosbuvir + RBV 24 weeks
Sofosbuvir Considerations
Can be considered in combination with
RBV in patients with GT1 who are not
eligible for PegIFN therapy
Sofosbuvir + RBV used for treatment of
chronic hepatitis in patients with
hepatocellular carcinoma awaiting
transplantation (up to 48 weeks or
transplant)
Sofosbuvir Dose
Dose: 400 mg daily with or without food
RBV is weight-based
< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg
in two divided doses with food
Severe renal impairment
No dose recommendations given for eGFR
< 30 mL/min/1.73m2 or ESRD
Higher exposure (up to 20-fold) of
predominant metabolite
Warnings/Precautions
Pregnancy
2 forms of non-hormonal birth control should
be used by women of childbearing potential
and their male partners during treatment and
for 6 months after end of treatment
Sofosbuvir P-gp Interactions P-gp Inducers
May significantly decrease sofosbuvir plasma concentrations
Avoid concomitant use of Rifampin and St. John’s wort
Other drugs with concern for P-gp interactions
Cyclosporine and sofosbuvir Increased AUC and Cmax in a single dose in a healthy volunteer,
but no change in pharmacokinetic parameters
Anticonvulsants Antimycobacterials HIV Protease Inhibitors
Carbamazepine Rifabutin Tipranavir/ritonavir
Phenytoin Rifapentine
Phenobarbital
Oxcarbazepine
Sofosbuvir
Pharmacokinetics Absorption
Peak plasma levels in 0.5-2 hours post-dose
Distribution 61-65% protein bound of drug, active metabolite
minimally protein bound
Metabolism Rapidly and extensively metabolized to active
GS-461203 which, when irreversibly dephosphorylated, forms inactive GS-331007
Elimination 80% urine, 14% feces, 2.5% expired air
Adverse Events
Most common (≥ 20%) ADE Sofosbuvir + RBV were fatigue and headache
Sofosbuvir + PegIFN + RBV were fatigue, headache, nausea, insomnia and anemia
Uncommon (<1%) but serious ADE Depression
Pancytopenia
Elevated bilirubin ○ Peaked at first 1-2 weeks of treatment and
returned to baseline by week 4
Isolated asymptomatic increases in creatine kinase and lipase
Neutrino
Open-label single arm trial evaluating 12-
weeks of treatment of sofosbuvir with
PegIFN and RBV in treatment naïve with
GT 1, 4, 5 or 6
N = 327
Median age 54 (19-70)
64% male
79% white, 17% black, 14% Hispanic or Latino
78% with baseline HCV RNA > 6 log10 IU/mL
89% GT1, 9% GT4, 2% GT5 or GT6
Neutrino Results Sofosbuvir + PegIFN alfa + RBV
12 wks
N = 327
Overall SVR 90% (295/327)
GT1 90% (261/292)
GT1a 92% (206/225)
GT1b 82% (54/66)
GT4 96% (27/28)
Outcomes for patients without SVR
On-treatment virologic
failure
0% (0/327)
Relapse 9% (28/326)
Other (i.e., lost to follow-
up)
1% (4/327)
92% of patients without cirrhosis versus 80% with cirrhosis achieved SVR
87% of blacks versus 91% of non-black achieved SVR
Fission
Randomized, open-label, active-controlled trial comparing 12 weeks of sofosbuvir + RBV compared with 24 weeks of PegIFN alfa 2a and RBV in treatment naïve patients with GT2 and GT3
N = 499 Median age 50 (19-77)
66% male
86% white, 3% black, 14% Hispanic or Latino
57% with baseline HCV RNA > 6 log10 IU/mL
72% GT3
Fission Results Sofosbuvir + RBV 12
weeks
N = 256
PegIFN + RBV 24
weeks
N = 243
Overall SVR 67% (171/256) 67% (162/243)
GT2 95% (69/73) 78% (52/67)
GT3 56% (102/183) 63% (110/176)
Outcome for patients
without SVR
On-treatment virologic
failure
< 1% (1/256) 7% (18/243)
Relapse 30% (76/252) 21% (46/217)
GT2 5% (4/73) 15% (9/62)
GT3 40% (72/179) 7% 17/243)
Other (eg, lost to follow-
up)
3% (8/256) 7% (17/243)
* Higher rates of SVR in non-cirrhotic patients for both GT2 and GT3
Positron
Randomized, double-blinded, placebo-controlled trial comparing 12 weeks of sofosbuvir with RBV compared to placebo in patients who were intolerant of interferon, ineligible or unwilling
N = 278 Median age 54 (21-75)
54% male
91% white, 5% black, 11% Hispanic or Latino
70% with baseline HCV RNA > 6 log10 IU/mL
16% with cirrhosis
49% with GT3
9% interferon intolerant, 44% ineligible, 47% unwilling
Positron Results Sofosbuvir + RBV 12
weeks
N = 207
Placebo 12 weeks
N = 71
Overall SVR 78% (161/207) 0% (0/71)
GT2 93% (101/109) 0% (0/34)
GT3 61% (60/98) 0% (0/37)
Outcome for patients
without SVR
On-treatment viro-
logic failure
0% (0/207) 97% (69/71)
Relapse 20% (42/205) 0% (0/0)
GT2 5% (5/107) 0% (0/0)
GT3 38% (37/98) 0% (0/0)
Other (eg, lost to
follow-up)
2% (4/207) 3% (2/71)
Fusion
Randomized, double-blinded trial that compared 12 and 16 weeks of treatment with sofosbuvir and RBV in patients who did not achieve SVR with prior IFN-based treatment (relapsers and nonresponders)
N = 201 Median age 56 (24-70)
70% male
87% white, 3% black, 9% Hispanic or Latino
73% with baseline HCV RNA > 6 log10 IU/mL
34% with cirrhosis
63% had GT3
75% were prior relapsers
Fusion Results
Sofosbuvir + RBV
12 weeks
N = 103
Sofosbuvir + RBV
16 weeks
N = 98
Overall SVR 50% (51/103) 71% (70/98)
GT2 82% (32/39) 71% (34/35)
GT3 30% (19/64) 62% (39/63)
Outcome for patients
without SVR
On-treatment virologic
failure
0% (0/103) 0% (0/98)
Relapse 48% (49/103) 29% (28/98)
GT2 18% (7/39) 11% (4/35)
GT3 66% (42/64) 38% (24/63)
Other (eg, lost to
follow-up)
3% (3/103) 0% (0/98)
Valence
Combination of weight-based RBV for treatment of GT2 or GT3 for treatment naïve or patients who did not achieve SVR with prior IFN therapy (including patients with compensated cirrhosis)
N = 419 Median age 51 (19-74)
60% male
87% white, 3% black, 9% Hispanic or Latino
Mean baseline HCV RNA was 6.4 log10 IU/mL
78% with GT 3
58% treatment-experienced ○ 65% experienced relapse/breakthrough to prior HCV
therapy
Valence Results
GT2
Sofosbuvir + RBV 12
weeks
N = 73
GT3
Sofosbuvir + RBV 2
weeks
N = 24
Overall SVR 93% (68/73) 84% (210/250)
Outcome for patients
without SVR
On-treatment viro-
logic failure
0% (0/73) <1% (1/250)
Relapse 7% (5/73) 14% (34/249)
Treatment-naïve 3% (1/32) 5% (5/105)
Treatment-
experienced
10% (4/41) 20% (29/144)
Other (eg, lost to
follow-up)
0% (0/73) 2% (5/250)
Resistance
From pooled clinical trial data There were some treatment emergent substitutions L159F
and S282T, some of which occurred in patients with virologic failure (breakthrough and relapse)
S282R and L320F substitutions detected by next generation sequencing also seen in one patient
Clinical significance unknown
Cross Resistance Sofosbuvir-associated resistance substitution of S282T
were still susceptible to NS5A and RBV
RBV-associated substitutions T 390 I and F415Y remained susceptible to sofosbuvir
Sofosbuvir remained active against HCV with resistance to NSA3/4A protease inhibitor, NS5B nonnucleoside inhibitor and NS5A inhibitor variants
Simeprevir (Olysio™)
NS3/4A protease inhibitor
Indicated for the treatment of chronic
hepatitis C Infection as a component of
a combination antiviral regimen
Combination with PegIFN and RBV for GT1
Infected patients with compensated liver
disease (including cirrhosis)
Simeprevir Considerations
Must not be used as monotherapy
HCV GT1a patients should be screened for the NS3 Q80K polymorphism and alternative therapy should be considered for patients Infected with the virus containing the Q80K polymorphism
Contains a sulfonamide moiety
Insufficient data to exclude an association between sulfa allergy and frequency/severity of observed adverse reactions
Simeprevir Dose
Dose: 150 mg daily with food Dosing recommendation for patient of East Asian
ancestry cannot be made
○ Higher simeprevir exposure and increase in adverse reactions
PegIFN and RBV dosed according to their package inserts
Dosing recommendation in patients with moderate to severe hepatic impairment cannot be made
No adjustment for renal impairment required
Efficacy has not been established in patients who have previously failed therapy with a treatment that includes simeprevir or other HCV protease inhibitors
Simeprevir/PegIFN/RBV
Duration of Treatment Treatment with
Simeprevir,
PegIFN, RBV
Treatment with
PegIFN, RBV
Total Treatment
Duration
Treatment-naïve
and prior
relapser patients
including those
with cirrhosis
First 12 week Additional 12
weeks 24 weeks
Prior non-
responder
patients
(including partial
and null
responders)
including those
with cirrhosis
First 12 weeks Additional 36
weeks 48 weeks
Stopping Rules/Response-
Guided Therapy HCV RNA Action
Treatment Week 4: ≥ 25 IU/mL Discontinue simeprevir, PegIFN
and RBV
Treatment Week 12: ≥ 25 IU/mL Simeprevir therapy completed.
Discontinue PegIFN and RBV
Treatment Week 24: ≥ 25 IU/mL Discontinue PegIFN and RBV
• Simeprevir must not be dose reduced or interrupted
• If therapy is discontinued secondary to adverse reactions or inadequate viral
response, simeprevir therapy cannot be reinitiated
• Dose adjustment/interruption of PegIFN and/or RBV secondary to adverse
events should be handled as outlined in their package inserts
Warnings/Precautions
Pregnancy
In female patients, do not initiate therapy
unless there is a recent report negative for
pregnancy
2 forms of non-hormonal birth control should
be used by women of childbearing potential
and their male partners during treatment and
for 6 months after end of treatment
Simeprevir Interactions
Avoid co-administration with moderate or
strong inducers or inhibitors of CYP3A4
Simeprevir
Pharmacokinetics Absorption
Peak plasma levels 4-6 hours post-dose
Distribution
99.9% protein-bound, primarily to albumin
Metabolism
Metabolized by CYP3A system, although CYP2C8 and CYP2C19 metabolism not excluded
Elimination
Biliary excretion
Adverse Events
Occur most frequently in within the first
4 weeks of therapy
Photosensitivity
Burning, erythema, exudation, blistering, edema
Limit sun exposure
Rash
Monitor for development of mucosal signs and
systemic complications
Dyspnea
Lab Abnormalities
Hyperbilirubinemia
Most frequently grade 1-2
Included elevation of both direct and indirect
Occurred early after therapy initiation
Peaked by week 2 in the study
Rapidly reversible upon simeprevir
discontinuation
Quest 1 and Quest 2
Randomized double-blind, placebo-controlled, 2-arm, multi-center trials in treatment-naïve patients 12 weeks triple therapy followed by 12 or 36
weeks of PegIFN/RBV
Pooled data Median age 47 years (18-73)
56% male
91% white, 7% black, 1% Asian, 17% Hispanic
78% had HCV RNA levels > 800,000 IU/mL
10% with cirrhosis
Quest 1 and Quest 2 Pooled
Results Treatment Outcome Simeprevir +
PegIFN/RBV
N = 521 % (n/N)
Placebo +
PegIFN/RBV
N = 264 % (n/N)
Overall SVR12 (GT1a and
1b)
GT1a
Without Q80K
With Q80K
GT1b
80 (419/521)
75 (191/254)
84(138/165)
58 (49/84)
85 (228/267)
50 (132/264)
47 (62/131)
43 (36/83)
52 (23/44)
53 (70/133)
Outcomes for all subjects
without SVR 12
On Treatment Failure
Viral Relapse
8 (42/521)
11 (51/470)
33 (87/264)
23 (39/172)
* SVR rates by Metavir Fibrosis Score:
F0-2 84% with simeprevir vs 55% PegIFN/RBV alone
F3-4 68% with simeprevir vs 36% PegIFN/RBV alone
Promise
Randomized, double-blind, placebo-controlled, 2-arm, multicenter study of patients with HCV GT1 who relapsed after prior IFN-based therapy 12 week of triple therapy followed by 12 or 36
weeks of PegIFN/RBV
Median age 52 years (20-71)
66% male
94% white, 3% black, 2% Asian, 7% Hispanic
84% had HCV RNA levels > 800,000 IU/mL
15% with cirrhosis
Promise Results
Treatment Outcome Simeprevir +
PegIFN/RBV
N = 260 % (n/N)
Placebo +
PegIFN/RBV
N = 133 % (n/N)
Overall SVR12 (GT1a
and 1b)
GT1a
Without Q80K
With Q80K
GT1b
79 (206/260)
70 (78/111)
78(62/79)
47 (14/30)
86 (128/149)
37 (49/133)
28 (15/54)
26 (9/34)
30 (6/20)
43 (34/79)
Outcomes for all
subjects without SVR
12
On Treatment Failure
Viral Relapse
3 (8/260)
18 (46/249)
27 (36/133)
48 (45/93)
* SVR rates by Metavir Fibrosis Score:
F0-2 82% with simeprevir vs 41% PegIFN/RBV alone
F3-4 73% with simeprevir vs 24% PegIFN/RBV alone
Aspire
Randomized, double-blind, placebo-controlled, 7-arm study of patients with HCV GT1 who failed prior therapy with PegIFN/RBV
12, 24 or 48 weeks of 100 mg or 150 mg of simeprevir in combination with 48 weeks of PegIFN and RBV or placebo with PegIFN and RBV Median age 50 years (20-69)
67% male
93% white, 5% black, 2% Asian
86% had HCV RNA levels > 800,000 IU/mL
18% with cirrhosis
Aspire Results Treatment Outcome 150 mg Simeprevir 12
weeks + PegIFN/RBV
N = 66 % (n/N)
Pooled 100 and 150
mg Simeprevir 12
weeks + PegIFN/RBV
N = 132 % (n/N)
Placebo +
PegIFN/RBV
N = 66 % (n/N)
SVR 24
Prior relapser 77 (20/26) 83 (44/53) 37 (10/27)
Prior partial responder 65 (15/23) 67 (31/46) 9 (2/23)
Prior null responder 53 (9/17) 45 (15/33) 19 (3/16)
Outcome for all subjects without SVR 24
On-treatment virologic failure
Prior relapser 8 (2/26) 6 (3/53) 22 (6/27)
Prior partial responder 22 (5/23) 20 (9/46) 78 (18/23)
Prior null responders 35 (6/17) 36 (12/33) 75 (12/16)
Viral Relapse
Prior relapser 13 (3/23) 8 (4/49) 47 (9/19)
Prior partial responder 6 (1/17) 8 (3/36) 50 (2/4)
Prior null responders 18 (2/11) 20 (4/20) 25 (1/4)
AASLD/IDSA Guidelines Genotype Recommended Alternative NOT RECOMMENDED
1 IFN Eligible: SOF + PEG/RBV x
12 weeks
IFN Ineligible: SOF + SMV ± RBV
x 12 weeks
IFN Eligible: SMV x 12 weeks +
PEG/RBV x 24 weeks
IFN Ineligible: SOF + RBV x 24
weeks
TVR + PEG/RBV x 24 or 48 weeks
(RGT)
BOC + PEG/RBV x 28 or 48 weeks
(RGT)
Monotherapy with PEG, RBV, or a
DAA
Do not treat decompensated
cirrhosis with PEG or SMV
2 SOF + RBV x 12 weeks None PEG/RBV x 24 weeks
Monotherapy with PEG,, RBV or a
DAA
Any regimen with TVR, BOC, SMV
3 SOF + RBV x 12 weeks SOF + PEG/RBV x 12 weeks PEG/RBV x 24-48 weeks
Monotherapy with PEG, RBV or a
DAA
Any regimen with TVR, BOC, SMV
4 IFN eligible: SOF + PEG/RBV x 12
weeks
IFN Ineligible: SOF + RBV x 24
weeks
SMV x 12 weeks + PEG/RBV x 24-
48 weeks
PEG/RBV x 48 weeks
Monotherapy with PEG, RBV or a
DAA
Any regimen with TVR, BOC, SMV
5 or 6 SOF + PEG/RBV x 12 weeks PEG/RBV x 48 weeks Monotherapy with PEG, RBV or a
DAA
Any regimen with TVR, BOC, SMV
Daclatasvir
NS5A replication complex inhibitor
Given 60 mg once daily
Studied in combination with SOF with and
without RBV in 100 GT1 naïve or previously
treated, non-cirrhotic and cirrhotic patients
○ SVR12 ranged from 95-100%
Adverse effects
○ Nausea, anemia, URI, headache
Anemia higher in groups with RBV
Ledipasvir
NS5A replication complex inhibitor
Given 60 mg once daily
○ Combination SOF and LED tablet is coming!
Studied in combination with SOF in 88
previously treated or untreated patients with
chronic HCV
○ SVR12
98% of GT1, 92% of GT2, 89% of GT3
Adverse effects
○ Headache, diarrhea, nausea
The Pipeline
http://www.pipelinereport.org/2013/hcv
HCV Treatments in Phase II
and
Phase III Studies Nucleoside/nucleotide polymerase inhibitors
Sofosbuvir, mericitabine, VX-135
Non-nucleoside polymerase inhibitors ABT-333, BI 207127, GS-9669, setrobuvir, VS-222, TMC 647055
NS5A Inhibitors ABT-267, daclatasvir, ledipasvir, ACH-3102, GS-5816,
GSK 2336805, IDX 719, MK-8742
2nd Generation Protease Inhibitors ABT-450/r, asunaprevir, faldaprevir, simeprevir, danoprevir/r, GS-
9451, MK-5172, sovaprevir
MicroRNA-targeting Miravirsen
Fixed Dose Combinations ABT-267/ABT-450/
Screening Guidelines
CDC Perform routine counseling, testing and appropriate follow-up for
persons at increased risk ○ IV drug users ○ Patients with conditions associated with high prevalence of HCV
HIV Patients who have received clotting factor concentrates prior to 1987 Patients on hemodialysis Unexplained aminotransferase elevation
○ Children born to HCV-infected mothers ○ Receipt of blood transfusion or organ transplant prior to July 1992 ○ Health care workers after needle stick or mucosal exposure to HCV
nucleic acid ○ Current sexual partners of HCV-infected persons
Anyone born between 1945 and 1965 ○ Estimated 800,000 undiagnosed cases in Baby Boomers
Second Generation DAA
Issue
References
Ghany, M. G., Nelson, D. R., Strader, D. B., Thomas, D. L. and Seeff, L. B. (2011), An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology, 54: 1433–1444.
Olysio® [package insert]. Titusville, NJ: Janssen Products; 2013.
Sovaldi® [package insert]. Foster City, Ca: Gilead Sciences, Inc.; 2013.
Victrelis® [package insert]. Whitehouse Station, NJ: Merck, Sharp & Dhome, Corp; 2011.
Incivek® [package insert]. Cambridge, MA: Vertex Pharmaceuticals, Inc.; 2013.
• Thompson AJ, et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology. 2010;139-120-129.
• Hoofnagle JH. Course and outcome of hepatitis C. Hepatology 2002;36:S21-S29
Teresa M. Cavanaugh, PharmD, MS, BCPS
Assistant Professor of Pharmacy Practice,
James L. Winkle College of Pharmacy,
University of Cincinnati
Transplant Pharmacist, Liver Transplant Clinic,
University of Cincinnati Medical Center