Hepatitis C Therapies In the Modern Era: Review for Front-Line Clinicians · 2019. 12. 16. ·...
Transcript of 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
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
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
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
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
• 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
Assessment Question 2
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
Slide credit: clinicaloptions.com
*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
Slide credit: clinicaloptions.com
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
Assessment Question 2
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
Assessment Question 2
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
• 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
• 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
Assessment Question 3
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.
Slide credit: clinicaloptions.com
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
Assessment Question 3
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
Assessment Question 3
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