Idea Transcript
12/8/17
Disclosure
Pharmacology for all HCV Clinicians
• I have nothing to disclose.
Parya Saberi, PharmD, MAS Assistant Professor, UCSF Center for AIDS Prevention Studies Medical Management of HIV/AIDS and Hepatitis December 2017
Resources
https://www.hcvguidelines.org/
• AASLD/IDSA: www.hcvguidelines.org • EASL: www.easl.eu/medias/cpg/HCVrecommendations/English-report.pdf
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Selecting & Refining HCV Treatment Options
Resources • University of Liverpool:
Patients being considered for HCV therapy
– HEP iChart: play.google.com/store/apps – HCV drug-drug interactions: www.hepdruginteractions.org – HIV drug-drug interactions: www.hivdruginteractions.org
Determine all possible DAA options based on genotype, presence of cirrhosis, treatment-naïve or -experienced, & drug resistance Review all prescription & OTC meds & herbal supplements
• Toronto General Hospital’s HCV drug-drug interaction tables & news: www.hcvdruginfo.ca/ • Indiana University’s CYP drug interaction table: Medicine.iupui.edu/clinpharm/ddis • Package inserts
Screen for interactions using resources & package inserts Refine DAA options based on interactions, prior AEs, & patient preferences
Case #1
Quick DAA Recap Brand
Epclusa
Generic
sofosbuvir (SOF) + velpatasvir (VEL) Harvoni sofosbuvir (SOF) + ledipasvir (LDV) Mavyret glecaprevir (GLE) + pibrentasvir (PIB) Vosevi sofosbuvir (SOF) + velpatasvir (VEL) + voxilaprevir (VOX) Zepatier elbasvir (EBR) + grazoprevir (GZR)
MOA
NS5B inhibitor + NS5A inhibitor NS5B inhibitor + NS5A inhibitor NS3/4A protease inhibitor + NS5A inhibitor NS5B inhibitor + NS5A inhibitor + NS3/4A protease inhibitor NS5A inhibitor + NS3/4A protease inhibitor
Gt
HD Decomp. EFV/ETR PI/r Cirrhosis /c
1, 2, 3, 4, 5, 6 1, 4, 5, 6 1, 2, 3, √ 4, 5, 6 1, 2, 3, 4, 5, 6 1, 4
√
√ √
√ √
√ (√) (√)
A 52 year-old African American woman comes in for her appointment with the clinical pharmacist to start SOF/VEL (Epclusa). • HCV: Tx-naïve, Gt 1a, stage 2 fibrosis, no cirrhosis (APRI= 0.3) • Labs: Normal liver function, CrCl= 63 • Meds: – TDF/FTC/EFV: 1 tablet once-daily – Omeprazole: 20mg once-daily
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Case #1 Recommended Treatment Options:
Question #1: Which ARVs have a major drug-drug interaction with SOF/VEL?
Tx-Naïve, HCV Gt 1a, not cirrhotic Regimens
Dose
Duration
EBR/GZR* QD fixed-dose combo EBR(50mg)/GZR (100mg)
x12 weeks
GLE/PIB
QD fixed-dose combo GLE (300mg)/PIB (120mg)
x8 weeks
SOF/LDV
QD fixed-dose combo SOF (400mg)/LDV (90mg)
x12 weeks
SOF/VEL
QD fixed-dose combo SOF (400mg)/VEL (100mg) x12 weeks
a. b. c. d. e.
Efavirenz Darunavir/r Tenofovir alafenamide Elvitegravir/c All of the above
*If no baseline NS5A RAVs detected (for EBR)
Mechanism of SOF/VEL Drug-Drug Interactions • SOF: substrate for P-gp & BCRP VEL: substrate for P-gp, BCRP, OATP, CYP3A4, CYP2C8, & CYP2B6 P-glycoprotein: efflux enzyme that “pushes” drugs out of GI blood stream back into GI lumen; also in liver, kidneys, & blood-brain barrier
Breast Cancer Resistance Protein: expressed in small intestine, liver, kidneys, & bloodbrain barrier & plays important role in drug disposition & tissue protection
Organic anion transporting polypeptide: involved in secretion or reabsorption of drugs (organic anions); across cell membrane in kidneys, brain, & liver
Cytochrome P450 Enzymes: >50 enzymes essential for metabolism of 2/3 of meds cleared by metabolism. Primary cause of drug-drug & drugfood interactions
Mechanism of SOF/VEL Drug-Drug Interactions • SOF: substrate for P-gp & BCRP VEL: substrate for P-gp, BCRP, OATP, CYP3A4, CYP2C8, & CYP2B6 • Inducers of P-gp, CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, St. John’s wort, EFV) ↓ plasma concentrations of SOF or VEL – Not recommended
• VEL is inhibitor of P-gp, BCRP, & OATP – Co-administration of substrates of these transporters may increase exposure of such drugs
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VEL-EFV Interaction • VEL: substrate of CYP3A4 • VEL + EFV: ~50% decrease in VEL exposure
Summary: SOF/VEL-ARV Interactions Drug Class Drug Name NNRTIs RPV EFV, ETR PIs DRV/r, ATV/r, LPV/r InSTI RAL EVG/c/FTC/TDF DTG N(t)RTI TDF/FTC ABC/3TC
Recommendation No dose adjustments needed Not recommended No dose adjustments needed No dose adjustments needed No dose adjustments needed No dose adjustments needed No dose adjustments needed No dose adjustments needed
Mogalian E, Luetkemeyer A, et al. AIDS 2016; Durban, South Africa.
Case #1: OTC Interactions 52 y/o woman, tx-naïve, Gt 1a, no cirrhosis, CrCl=63, on TDF/FTC/EFV
You ask her about any OTCs & she reminds you that she is taking omeprazole 20mg once daily for reflux.
Question #2: What should you tell her about omeprazole? a. b. c. d.
Nothing Try to avoid acid blockers but, if you must, take SOF/VEL with food & 4 hours before OMP Try to avoid acid blockers but, if you must, take OMP 40mg once daily Take famotidine or antacids instead of OMP, given lack of interactions
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VEL-OMP Interaction • ↑pH results in ↓VEL solubility &↓VEL concentration • Try to avoid acid blockers altogether… – PPIs: SOF/VEL with food & 4 hrs before PPI (at max dose comparable to omeprazole 20mg) – H2-RAs: Given simultaneously with or 12 hours apart from SOF/VEL at ≤ famotidine 40mg BID – Antacid: Separate by 4 hours
Case #1: Options 1. Change ART to non-EFV-containing regimen (e.g., DTG) – She tried ABC/3TC/DTG before & had severe insomnia, so she refuses any ART change OR
2. Change DAA – EBR/GZR & GLE/PIB (substrates of CYP3A & P-gp): incompatible with EFV
– Decide to try SOF/LDV (Harvoni)
Mechanism of SOF/LDV Drug-Drug Interactions • SOF/LDV: substrates of drug transporters P-gp & BCRP • P-gp inducers (e.g., rifampin, St. John’s wort): may ↓SOF/LDV plasma concentrations – not recommended
• Clinically significant interactions mediated by CYP450 or UGT1A1 enzymes are not expected
Question #3: Which ARV regimens have drug-drug interactions with SOF/LDV? a. b. c. d. e.
DTG/ABC/3TC Any TDF-containing regimens Any HIV PI/r-based regimens Any TAF-containing regimens Any NNRTI-based regimens
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TDF & SOF/LDV
TAF & SOF/LDV
• Possible mechanism: – LDV inhibits efflux transporters (P-gp & BCRP) leading to ↑TFV exposure – In vitro, SOF/LDV increase TFV absorption
SOF/LDV does not significantly impact TAF or TFV PK
• ↑TFV not been shown to be clinically significant. Options: – Switch to TAF (especially if preexisting renal dysfunction) – Monitor renal function more closely if continue TDF
ARV
TFV PK
INSTI
• TFV AUC ↑1.7-fold in DTG+TDF/FTC
NNRTI • TFV AUC ↑98% in EFV/TDF/FTC • TFV AUC ↑40% in RPV/TDF/FTC PI/r
• TFV AUC ↑50% in DRV/r+TDF/FTC • Unchanged with 12-hour staggering of dose
AUC: area under the concentration drug concentration-time curve; DRV: darunavir; FTC: emtricitabine; PK: pharmacokinetics; r: ritonavir; TDF: tenofovir
German P, et al. Abstract O_06. 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. 2014; Washington, DC. / German P, et al. Abstract 82. 22nd CROI. 2015; Seattle, WA. / Mathias A. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. 2015; Washington, DC.
Side Note: SOF/VEL + TDF or TAF
Custodio JM, et al. IDSA/IDWeek 2015; San Diego, CA.
Summary: SOF/LDV-ARV Interactions Drug Class NNRTIs PIs
• SOF/VEL + TDF: increased TFV AUC by 20-81% – Recommend: monitor renal function or change TDF
• SOF/VEL + TAF: no clinically significant impact on TFV
Drug Name EFV, ETR, NVP, RPV ATV/r, DRV/r, LPV/r TPV ELV/c
Recommendation No dose adjustments needed No dose adjustments needed Not recommended InSTI Monitor for TDF-associated renal dysfunction COBI levels ↑ (possible ↑AEs) DTG, RAL No dose adjustments needed N(t)RTI TDF+EFV Monitor for TDF-associated renal dysfunction TDF+ (ATV/r or DRV/r ↑TDF concentrations. Consider alternative therapy; or LPV/r) monitor for TDF-associated renal dysfunction TAF No dose adjustments needed 3TC, ABC, FTC, ZDV No dose adjustments needed CCR5 Inhibitor MVC No data
Only DAA compatible with EFV (& likely with ETR)
Mogalian E, Luetkemeyer A, et al. AIDS 2016; Durban, South Africa.
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LDV-OMP Interaction • ↑pH results in ↓LDV solubility. Drugs that ↑pH will ↓LDV concentration. • PPIs: – When omeprazole 20mg/day given 2hrs prior to LDV, ↓LDV AUC by 42% & ↓LDV Cmax by 48% – Try to avoid acid blockers. If necessary, give PPI simultaneously with SOF/LDV, under fasted conditions, & at dose comparable to omeprazole ≤20mg/day
• H2-RA: Give simultaneously with or 12hrs apart from SOF/LDV; at famotidine ≤ 40mg BID • Antacid: Separate by 4hrs
Case #1: Conclusion • Pt willing to try TAF/FTC + EFV, so you change her ARVs. – Recommend monitoring x1-2 months on new ART before starting DAAs
• She does very well on SOF/LDV & has attained SVR12.
Case #1: Options
52 y/o woman, tx-naïve, Gt 1a, no cirrhosis, CrCl=63, on TDF/FTC/EFV & Omeprazole 1. Change TDF to avoid TDF + SOF/LDV interaction – TDF/FTC to ABC/3TC (if HLA-b5701 negative) – TDF/FTC to TAF/FTC
2. Continue TDF/FTC/EFV + SOF/LDV & monitor renal function very closely - e.g., every 2 weeks at least initially (Cr, electrolytes w/phosphorus, & urinary protein & glucose)
3. Use other DAA regimen: issues with cost/access, pill burden, AEs
Case #2 A 45 year-old male patient is being seen at the clinical pharmacy office to get started on GLE/PIB (Mavyret). • HCV: Tx-naïve, Gt1b, cirrhotic (Child-Pugh Reminder: score A) GLE/PIB can’t be used in • Meds: TAF/FTC/EVG/c, rosuvastatin, decompensated cirrhosis (i.e., omeprazole Child-Pugh B/C)
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Case #2 Recommended Treatment Options:
Tx-Naïve, HCV Gt 1b, compensated cirrhosis Regimens
Dose
Duration
GLE/PIB
QD fixed-dose combo GLE (300mg)/PIB (120mg)
x12 weeks
EBR/GZR
QD fixed-dose combo EBR(50mg)/GZR (100mg)
x12 weeks
SOF/LDV
QD fixed-dose combo SOF (400mg)/LDV (90mg)
x12 weeks
SOF/VEL
QD fixed-dose combo SOF (400mg)/VEL (100mg) x12 weeks
Question #4: Which ARV is GLE/PIB compatible with? a. b. c. d. e.
Atazanavir/r Elvitegravir/c Efavirenz or Etravirine Raltegravir or Dolutegravir All of the above
GLE/PIB ↑ELV/c Cmax by 29-36%, AUC by 42-47%. GLE Cmax & AUC 2.5- & 3.1-fold higher, respectively, vs. GLE/PIB alone; PIB AUC was 57% higher. No clinical data for ELV/c + GLE/PIB, so caution when using together.
Question #4: Which ARV is GLE/PIB compatible with? a. b. c. d. e.
Atazanavir/r Elvitegravir/c Efavirenz or Etravirine Raltegravir or Dolutegravir All of the above
Effect of Inhibitors on GLE/PIB
• GLE/PIB contraindicated with ATV/r • GLE/PIB may be okay with DRV/r, LPV/r, and ELV/c but not recommended due to lack of clinical data
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Summary: GLE/PIB-ARV Interactions GLE/PIB: CYP3A & P-gp substrates Drug Class Drug Name
Recommendation
NNRTIs
RPV
No dose adjustments needed
EFV, ETR
Not recommended
ATV/r
Not recommended
DRV/r, LPV/r
Not recommended (for now)
RAL
No dose adjustments needed
DTG
No dose adjustments needed
ELV/c
Not recommended (for now)
TDF, TAF
No dose adjustments needed
PIs InSTI
N(t)RTI
Case #2: DAA + PPI Interactions No statistically significant difference in SVR12 between high & low PPI doses with GLE/PIB across genotypes, but caution with high dose PPIs until more data available
Flamm S, et al. World Congress of Gastroenterology at ACG 2017; 2017; Orlando, FL. P1435.
SOF/LDV Antacids Separate by 4 hrs H2RA Together or 12hrs apart; FAM 40mg BID PPIs Together with OMP 20mg
SOF/VEL EBR/GZR GLE/PIB SOF/VEL/VOX Separate by 4 hrs Separate by 4 hrs Together or 12hrs Together or 12hrs apart; FAM 40mg BID apart; FAM 40mg BID With food, 4hrs With food, 4hrs before OMP 20mg before OMP 20mg
Case #2: Drug-Drug Interactions • GLE/PIB inhibit BCRP, P-gp, OATP • Rosuvastatin (substrate for BCRP & OATP) – Cmax ↑462%, AUC ↑115% – Do not exceed 10mg/d
• Pravastatin: reduced dose by 50% • Atorvastatin: do not co-administer Atorvastatin Pitavastatin Pravastatin Rosuvastatin
SOF/LDV ND ND
SOF/VEL ND 10mg
EBR/GZR 20mg 10mg
GLE/PIB Lowest dose ↓dose by 50% 10mg
SOF/VEL/VOX 40mg
Side Note: Warfarin • Updated SOF, SOF/LDV, SOF/VEL, SOF/VEL/VOX: “Fluctuations in INR values may occur in patients receiving warfarin concomitant with HCV treatment... Frequent monitoring of INR values is recommended during treatment and post-treatment...” • Interaction more significant with ribavirin & PrOD • Interaction usually results in decreased INR, needing an ↑Warfarin dose (≥15%) • Mechanism unclear but eradication of HCV improves liver function to increase clotting factor synthesis &/or warfarin metabolism
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Case #2: Options
Case #2: Conclusion
45 y/o man starting GLE/PIB. Gt1b, cirrhotic, Txnaïve; TAF/FTC/EVG/c, rosuvastatin, omeprazole
1. Change ART – Suggestions: DTG/ABC/3TC or RPV/TAF/FTC or
2. Change DAA – SOF/LDV x12 weeks – SOF/VEL x12 weeks
Contraindicated with PPIs
Case #3 You’re seeing a 58 year-old White male on hemodialysis who would like to start HCV treatment. Provider is not sure what to use given patient’s renal function. – HCV: Tx-naïve, Gt 3, no cirrhosis – Meds: DTG + ABC + 3TC (renally-dosed)
• Due to insurance coverage of GLE/PIB, we decide to change ART to DTG/ABC/3TC. – Recommend monitoring x1-2 months on new ART before starting DAAs
• Patient recently started HCV treatment & is doing well.
Question #5: Which DAA agents are okay to use in those with eGFR 90 mL/min); 2= mild CKD (eGFR 60-89 mL/min); 3= moderate CKD (eGFR 30-59 ml/min) 4= severe CKD (eGFR 15-29 mL/min); 5= end-stage CKD (eGFR