hepatitis c therapies in the modern era: review for front-line clinicians · 2019. 12. 16. ·...

Hepatitis C Therapies In the Modern Era: Review for Front-Line Clinicians

Lindsey Buscemi Lipinski, PharmD, BCPS, AAHIVP

Infectious Diseases Clinical Pharmacist, UVA Health System

September 20, 2019

Disclosures

• None

Objectives

• Review pre-treatment workup for HCV

• Identify current treatment options for HCV

• Select appropriate direct-acting antiviral (DAA) therapy for HCV based on genotype, presence of cirrhosis, and other patient specific factors

• Describe caveats of HCV therapy including drug interactions, dosing considerations, and adverse effects

Patient Case

• 62-yr-old African-American female with history of HTN and hyperlipidemia was diagnosed with HCV by her PCP

• Risk factor for HCV: past history of injection drugs, has not injected in > 10 yrs

Assessment Question 1

What labs and tests should be obtained?

A. Viral load and genotype

B. Fibroscan

C. CBC, CMP

D. HBV, HAV, HIV serologies

E. All of the above

HCV Pretreatment Workup

Determine Genotype and Viral

Load

Evaluate Liver

Disease

Determine HCV

Treatment History

Other IssuesSpecial

population

DDIs

Contraindications

Insurance Preference

HCV Treatment

and Duration

Slide credit: clinicaloptions.com

http://www.clinicaloptions.com/

Factors That Influence HCV TreatmentCategory Factors

Viral HCV GT Viral load

Treatment

HCV treatment history– PegIFN + RBV– Protease inhibitor– Sofosbuvir– NS5A

RBV eligibility Resistance

Fibrosis stage Ranges F0-F4 Compensated vs. decompensated cirrhosis Transplant evaluation if necessary

Comorbidities HIV, HBV/HAV coinfection Cardiovascular, renal, neurologic comorbidities Drug–drug interactions

Financial Insurance approval

Patient specific Treatment readiness Substance use


What labs and tests should be obtained?

A. Viral load and genotype

B. Fibroscan

C. CBC, CMP

D. HBV, HAV, HIV serologies

E. All of the above

Patient Case



• Laboratory results include

• HCV RNA 6.2 million IU/mL, HCV genotype 1a

• Bilirubin 0.6 mg/dL, ALT 54 IU/L, AST 47 IU/L, CrCl 65 mL/min

• FibroSure F2

• HBsAg negative, HBcAb total negative, hepatitis A antibody negative, HIV negative

• Ultrasound abdomen: unremarkable

• Medications to be reviewed in clinic


What is an appropriate treatment regimen for our patient at this time?

A. EBR/GZR x 12 weeks

B. LDV/SOF x 8 weeks

C. GLE/PIB x 8 weeks

D. SOF/VEL/VOX x 12 weeks

HCV Viral Life Cycle

Sarpel et al. Clinical Pharmacist;7 Aug 2017.

Hepatitis C Treatment: ThenInterferon

• Daily interferon injections + weight-based ribavirin initially, then transitioned to weekly pegylatedinterferon + daily RBV

• No direct effect on virus, just modulated immune system

• Severe ADRs: flu-like symptoms, depression, anemias, GI, fatigue

• Low SVR rates (~40%)

Protease Inhibitors

• Telaprevir and Boceprevir FDA approved 2011

• Added to IFN + RBV regimens for 24-48 weeks

• Only marginally increased SVR rates

• Severe toxicities including SJS

• Significant CYP drug interactions and food requirement

Sofosbuvir (Sovaldi)

• FDA approved late 2013

• Initially approved with IFN + RBV (GT1,4) or RBV alone (GT2,3)

• Did not reduce ADRs from IFN/RBV but SVR rates reached 90%

Impact of HCV Regimens on SVR Rate

• Hepatitis C Cure = sustained virologic response (SVR)

• Viral load after patient has been off of completed therapy for 12 (SVR12) or 24 (SVR24) weeks

• Most clinical trials and guidelines measure SVR12

HCV Treatment Now: DAA Regimens

Regimen Component Classes Dosing Approved GT

Glecaprevir/pibrentasvir(Mavyret)

Protease inhibitor + NS5A inhibitorGlecaprevir/pibrentasvir 300/120

mg 3 tablets QD1,2,3,4,5,6

Sofosbuvir/ledipasvir(Harvoni)

Polymerase inhibitor + NS5A inhibitorSofosbuvir/ledipasvir: 400/90 mg 1 tab QD

1, 4, 5, 6

Sofosbuvir/velpatasvir(Epclusa)

Polymerase inhibitor + NS5A inhibitorSofosbuvir/velpatasvir: 400/100 mg 1 tab QD

1, 2, 3, 4, 5, 6

Grazoprevir/elbasvir(Zepatier)

Protease inhibitor + NS5A inhibitor

Grazoprevir/elbasvir: 100/50 mg 1 tab QD

1, 4

Sofosbuvir/velpatasvir/voxilaprevir (Vosevi)

Polymerase inhibitor + NS5A inhibitor+ protease inhibitor

Sofosbuvir/velpatasvir/voxilaprevir400/100/100 mg QD

1,2,3,4,5,6

Sofosbuvir (Sovaldi) + daclatasvir (Daklinza)

Polymerase inhibitor + NS5A inhibitorSofosbuvir: 400 mg QDDaclatasvir: 60 mg QD

1, 3

Sofosbuvir (Sovaldi) + simeprevir (Olysio)

Polymerase inhibitor + protease inhibitor

Simeprevir: 150 mg QDSofosbuvir: 400 mg QD

1, 4

Paritaprevir/ritonavir/ ombitasvir + dasabuvir (Viekira Pak) or (Technivie)

Protease inhibitor + NS5A inhibitor +

polymerase inhibitor

Paritaprevir/RTV/ombitasvir: 150/100/25 mg QD

Dasabuvir: 250 mg BID 1 (Veikira), 4 (Technivie)

Many Options in 2019: AASLD/IDSA-Recommended Regimens for HCV

Regimen Approved Genotypes

Elbasvir/grazoprevir* 1, 4

Ledipasvir/sofosbuvir 1, 4, 5, 6

Sofosbuvir/velpatasvir 1, 2, 3, 4, 5, 6

Sofosbuvir/velpatasvir/voxilaprevir 1, 2, 3, 4, 5, 6

Glecaprevir/pibrentasvir* 1, 2, 3, 4, 5, 6

• Single-tablet or 3-tablet coformulations, all with daily dosing

• For every genotype, there is an effective treatment

• Newest treatments effective for all genotypes, with cure rates of 95% or higher, even without ribavirin


*Approved in advanced renal insufficiency and dialysis.

AASLD/IDSA HCV Guidance. 2018.

Treatment duration is 8-12 wks for essentially all treatment-naive patients


HCV Treatment Now: DAA Regimens

Glecaprevir/pibrentasvir(Mavyret)

Protease inhibitor + NS5A inhibitor

Glecaprevir/pibrentasvir300/120 mg 3 tablets QD

1,2,3,4,5,6

Sofosbuvir/velpatasvir(Epclusa)

Polymerase inhibitor + NS5A inhibitor

Sofosbuvir/velpatasvir: 400/100 mg 1 tab QD

1, 2, 3, 4, 5, 6

Regimen Component Classes Dosing Approved GT

Glecaprevir/Pibrentasvir (Mavyret)

• Pharmacology

• GLE: NS3/4A protease inhibitor

• PIB: NS5A inhibitor

• Inhibits viral replication/assembly

• Pharmacokinetics

• CYP3A

• No renal elimination (okay in CRD and hemodialysis)

• Dosing

• 3 tablets daily with food (better absorption)

• Selected drug interactions• Rifampin

• Anticonvulsants

• Some ART

• Selected contraceptives

• Statins

• St John’s wort

• Most common/important AEs• Headache, nausea, diarrhea

• Elevated bilirubin/ALT levels

• NOT recommended in Child-Pugh class B; contraindicated in Child-Pugh Class C Slide credit: clinicaloptions.comGlecaprevir/pibrentasvir PI.


Sofosbuvir/Velpatasvir (Epclusa)

• Pharmacology

• SOF: NS5B polymerase inhibitor

• VEL: NS5A inhibitor

• Inhibits viral replication

• Pharmacokinetics

• Eliminated by kidneys

• Not recommended if eGFR < 30 mL/min

• Dosing

• 1 tablet daily with or without food

• + Ribavirin

• Selected drug interactions

• Acid-reducing agents (antacids, PPIs, H2 blockers)

• Anticonvulsants (carbamazepine, oxcarbazepine, phenytoin)

• Rifampin

• St John’s wort

• Most common/important AEs

• Fatigue, headache, nausea

• Bradycardia (with amiodarone)

Slide credit: clinicaloptions.comSofosbuvir/velpatasvir PI.


AASLD/IDSA Recommendations: Initial Therapy for Genotype 1, 2, 3,4, 5 or 6 HCV Infection all include the following 2 treatment options


HCV GT No Cirrhosis Compensated Cirrhosis

1/2/3/4/5/6GLE/PIB (Mavyret) 8 wksSOF/VEL (Epclusa) 12 wks

GLE/PIB (Mavyret) 12 wksSOF/VEL (Epclusa) 12 wks*

*Only if no baseline Y93H for GT 3. If Y93H present for GT3, add RBV or choose alternative regimen

(consider SOF/VEL/VOX)

AASLD/IDSA. HCV guidance. 2018.


First-line HCV Therapy: Distinguishing Among Recommended Options

GLE/PIB - 3 tablets daily with food8 wks no cirrhosis, 12 wks if cirrhosis, GT 1-6

No RAS testing

Contains PI: do not use if decompensated

Can be used in stage 4/5 CKD

DDI highlights: statins, rifampin, some ART

SOF/VEL - single daily tablet12 wks, GT 1-6

Requires RAS testing for some GT 3

Safe in decompensation

Not recommended for stage 4/5 CKD

DDI highlights: acid-reducing agents, rifampin

DDIs are drug specific and there are many more to consider than are listed here.

Always check! https://www.hep-druginteractions.org/Slide credit: clinicaloptions.comAASLD/IDSA. HCV guidance. 2018.

Mavyret

Epclusa

https://www.hep-druginteractions.org/



What is an appropriate treatment regimen for our patient at this time?

A. EBR/GZR x 12 weeks

B. LDV/SOF x 8 weeks

C. GLE/PIB x 8 weeks

D. SOF/VEL/VOX x 12 weeks

Caveats of TreatmentDosing, drug interactions, adverse effects

Dosing Considerations in Renal Impairment

CrCl SOF/VEL GLE/PIB

30-50 mL/min

No adjustment No adjustment

15-30 mL/min

Safety and efficacy not established

No adjustment

<15 mL/min or HD

Safety and efficacy not established

No adjustment

*Small studies suggest that SOF can be used safety in patients with ESRD on HD but data is limited and

should be addressed on a case by case basis

AASLD/IDSA Guidelines. 2018.

SOF safety in ESRD: Studies

Desnoyer et al. 2016

• Full dose SOF (n=7) and 3x/weekly SOF (n=3) along with LDV, DCV, or RBV

• 8/10 achieved SVR12 or 24

• 9 ADRs reported in 7 patients: anemia, headache, itching, muscle weakness, cough, and anxiety (all grade 1)

• 1 grade 2 event of asthenia reported

Nazario et al. 2016

• 17 patients with ESRD (2 not on HD) received full dose SOF + SMV x 12 weeks

• All patients achieved SVR 12

• 4 patients reported ADR: headache, insomnia, n/v, anemia

Journal of Hepatology 2016;65:40–47 Liver Int. 2016; 36:798–801

Bottom Line: limited data and anecdotes support safety in this

population, but risk vs. benefit must be addressed in every patient

Drug Interactions

Patient Case



• Laboratory results include

• HCV RNA 6.2 million IU/mL, HCV genotype 1a

• Bilirubin 0.6 mg/dL, ALT 54 IU/L, AST 47 IU/L, CrCl 65 mL/min

• FibroSure F2

• HBsAg negative, HBcAb total negative, hepatitis A antibody negative

• Ultrasound abdomen: unremarkable

• Medications: lisinopril 10 mg/day, atorvastatin 20 mg/day


Since she will begin GLE/PIB, how should our patient’s other medications be managed?

A. Switch atorvastatin 20 mg to simvastatin 40 mg

B. Switch atorvastatin 20 mg to rosuvastatin 5 mg

C. Maintain atorvastatin 20 mg and monitor

D. Select a different HCV therapy

Great Resource: Hep Drug Interactions

• https://www.hep-druginteractions.org

Selected Potential Drug InteractionsConcomitant Medication SOF VEL GLE/PIB

Acid-reducing agents X

Amiodarone X X X

Anticonvulsants X X X

Digoxin X X

Ethinyl estradiol–containing products

X

Glucocorticoids

PDE5 inhibitors X

Rifamycin antimicrobials X X X

Sedatives

St John’s wort X X X

Statins X X

AASLD/IDSA Guidelines. April 2018.

X indicates drug interaction is present, may or may not reflect contraindication

DDIs With Acid Reducing Agents

HCV Regimen QD PPI* BID PPI H2 Blocker† Antacids

SOF/VEL[2]

Take SOF/VEL with food 4 hrs before omeprazole 20

mgNO

Take SOF/VEL + H2

blocker together or 12 hrs apart

Separate antacids and SOF/VEL by 4

hrs

GLE/PIB[4] No significant interaction NO[5] No data No data

1. Sofosbuvir/ledipasvir PI. 2. Sofosbuvir/velpatasvir PI. 3. Sofosbuvir/velpatasvir/voxilaprevir PI. 4. Glecaprevir/pibrentasvir PI. 5. Yu G. Lancet. 2017;17:1239.

*Not to exceed omeprazole 20 mg/day. †Not to exceed famotidine 40 mg BID.



Amiodarone

• Case reports of symptomatic bradycardia reported (including one fatal case) in patients receiving amiodarone with sofosbuvir ± another DAA• Occurred generally within hours to days but cases occurred up to 2 weeks in patients

maintained on amiodarone beginning SOF

• FDA briefing “For patients where there are no viable treatment alternatives and this combination must be used, the manufacturer recommends cardiac monitoring in an in-patient setting for the first 48 hours of coadministration. Outpatient or self-monitoring of heart rate should occur daily through at least the first 2 weeks of treatment and patients should be counseled about the risk of serious symptomatic bradycardia.” • Patients who recently discontinued amiodarone should be monitored similarly due

to the prolonged half-life

http://www.fda.gov/Drugs/DrugSafety/ucm439484.htm

StatinsSOF/VEL GLE/PIB

Atorvastatin Use lowest effective dose and monitor

Do not coadminister

Rosuvastatin Max dose 10 mg Max dose 10 mg

SimvastatinUse lowest

effective dose and monitor

Do not coadminister

Lovastatin Do not coadminister

Pravastatin n/a Max dose 20 mg

Pitavastatin Use lowest effective dose and monitor

Use lowest effective dose and monitor

AASLD/IDSA Guidelines. April 2018..

Managing Drug Interactions While on Treatment• Thorough medication reconciliation prior to treatment and at each visit

(includes OTCs and herbals!)

• For contraindicated medications/doses:• Weigh risk vs. benefit of stopping medication during HCV treatment• Determine urgency of HCV treatment – can it be deferred?• Lower dose and/or change agent during HCV treatment• Discuss permanent vs. temporary change

• What if you cannot avoid the interaction?• Optimize dose and separation strategies• Interruption of HCV treatment more likely to cause failure than administration with

concomitant drug interaction


Since she will begin GLE/PIB, how should our patient’s other medications be managed?

A. Switch atorvastatin 20 mg to simvastatin 40 mg

B. Switch atorvastatin 20 mg to rosuvastatin 5 mg

C. Maintain atorvastatin 20 mg and monitor

D. Select a different HCV therapy

Toxicity Monitoring

Adverse Effects and Precautions• Most DAA’s generally well-tolerated

• Fatigue, headache, nausea/vomiting, diarrhea, mild rash

• Black Box Warnings:• Bradycardia: Increased risk when SOF-based regimens administered with

amiodarone

• HBV Reactivation: on 10/4/16 FDA required all approved DAA’s to be given boxed warning about reactivation of Hepatitis B in patients receiving DAA treatment• Reported in patients with current and prior HBV infections

• Includes warning for providers to screen for HBV prior to treatment and to monitor for HBV reactivation during and after treatment

HBV Testing/Monitoring During HCV DAA Therapy

• Test all pts initiating HCV therapy for HBsAg, anti-HBc, and anti-HBs• Vaccinate if no HBV markers; follow flow chart below if HBV markers present

HBV DNA detectable

HBsAg negative;

anti-HBc positive

(± anti-HBs)

HBV DNA meets criteria

for treatment in AASLD

HBV guidelines

“Insufficient data

to provide clear

recommendations”

Can check HBV viral load

at weeks 4 and 12

(Consider HBV reactivation

if liver enzymes increase

unexpectedly)

HBV DNA low or

undetectable

Treat with HBV drug

Administer prophylactic

HBV drug until HCV SVR12

or monitor for reactivation

at regular intervals, treating

if HBV DNA > 10-fold above

BL or > 1000 IU/mL when

previously undetectable/

unquantifiable

HBsAg positive

AASLD/IDSA. HCV guidance. 2018. Slide credit: clinicaloptions.com


Ribavirin

• Severe depression and suicidality reported should screen patients for depression prior to and during treatment

• Anemia often requires dose reduction; reversible; may require supportive therapy if severe

• Hypersensitivity reactions

• Other: fatigue, irritability, insomnia, rash

Adverse effects

• Category X: teratogenicity and birth defects reported

• Females must have pregnancy test prior to treatment and monthly during treatment

• Females must use 2 methods of birth control throughout treatment

• Should counsel females and males on avoiding pregnancy/conception for 6 months after completing treatment

Pregnancy risk

Ribavirin PI.

Managing Treatment-Emergent Adverse Effects• Assess causality

• Careful assessment of timelines • Utilize labeling, clinical trials, case reports• Realize vague, non-specific symptoms may be difficult to tease out from other causes

• Assess risks vs. benefit of stopping therapy

• Utilize supportive care• Antiemetics, OTC pain medications, antihistamines/topical therapies• RBV-induced anemia may require dose modification and/or pharmacotherapy in

extreme cases• Change time of dosing

Monitoring During Therapy

• Laboratory monitoring: AASLD/IDSA Guidelines• HCV viral load at week 4 and 12 weeks after therapy completion (SVR)

• HBV viral load checked at weeks 4 and 12 for HBcAb+

• More frequent assessment of drug-related ADRs as clinically indicated

• Adherence and ADRs• Patients should be assessed for ADRs at every visit

• Adherence should be assessed at every visit

• Medication list should be reviewed at every visit

AASLD/IDSA Guidelines. 2018..

Patient Education Pearls• Encourage healthy liver habits

• Avoid medications, including OTC and herbals, that may harm liver• Avoid excess Tylenol use (≤2 grams/day)• Avoid alcohol use• Coffee is good for the liver!• Encourage healthy diet and weight management

• Encourage patients that newer treatments have significantly less side effects than IFN/RBV regimens

• Transmission education• A cure is not protective—patients can be re-infected so it is important to avoid behaviors that

may cause reinfection • Avoid sharing personal hygiene items (toothbrushes, razors, or nail clippers) • Cover cuts and sores on the skin to keep from spreading infectious blood• Blood-borne virus—not spread by casual contact, sharing utensils, coughing or sneezing—help

stop the stigma!

Conclusions

• Vast majority of HCV infections curable

• Multiple regimens highly effective and safe across HCV genotypes• Every genotype has a treatment option

• Modern therapies are well-tolerated

• Regimens should be selected based on patient specific parameters including genotype, presence of cirrhosis, past treatment history, drug interactions, and adverse effect profile.

• Drug interactions are present, but available tools can assist with detection and management.

Hepatitis C Therapies In the Modern Era: Review for Front-Line Clinicians

Lindsey Buscemi Lipinski, PharmD, BCPS, AAHIVP

Infectious Diseases Clinical Pharmacist, UVA Health System

September 20, 2019

hepatitis c therapies in the modern era: review for front-line clinicians · 2019. 12. 16. ·...

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