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