Disclosure HCV Pharmacology for • I have nothing to disclose. All Clinicians Parya Saberi, PharmD, MAS Assistant Professor, UCSF Center for AIDS Prevention Studies Medical Management of HIV/AIDS and Hepatitis December 2018 Resources Resources • University of Liverpool: • AASLD/IDSA: – HEP iChart: www.hcvguidelines.org https://play.google.com/store/apps/details?id=com.liverpool uni.icharthep • EASL: http://www.easl.eu/research/our ‐ – HCV drug ‐ drug interactions: www.hep ‐ druginteractions.org contributions/clinical ‐ practice ‐ guidelines • Toronto General Hospital’s HCV drug ‐ drug interaction tables & news: www.hcvdruginfo.ca/ • Package inserts
Selecting & Refining HCV Treatment Options Patients being considered for HCV therapy Determine all possible DAA options based on genotype, presence of cirrhosis, treatment ‐ naïve or ‐ experienced, & drug resistance Review all prescription & OTC meds & herbal supplements Screen for interactions using resources & package inserts Refine DAA options based on interactions, 2 new ARVs (bictegravir & doravirine): limited data for BIC but looks compatible with all DAAs. prior AEs, & patient preferences DOR is compatible with all DAAs. https://www.hcvguidelines.org/unique ‐ populations/hiv ‐ hcv Quick DAA Recap Case #1 Brand Generic MOA Gt HD Decomp. EFV/ PI/r /c A 52 year ‐ old African American woman comes Cirrhosis ETR Epclusa sofosbuvir (SOF) + NS5B inhibitor + 1, 2, 3, in for her appointment with the clinical √ √ velpatasvir (VEL) NS5A inhibitor 4, 5, 6 pharmacist to start SOF/VEL (Epclusa) . Harvoni sofosbuvir (SOF) + NS5B inhibitor + 1, 4, 5, √ √ √ ledipasvir (LDV) NS5A inhibitor 6 • HCV: Tx ‐ naïve, Gt 1a, stage 2 fibrosis, no Mavyret glecaprevir (GLE) + NS3/4A protease inhibitor + 1, 2, 3, √ CTP ‐ A ( √ ) cirrhosis (APRI= 0.3), HCV VL= 10 million pibrentasvir (PIB) NS5A inhibitor 4, 5, 6 Vosevi sofosbuvir (SOF) + NS5B inhibitor + 1, 2, 3, • Labs: Normal liver function, CrCl= 75 velpatasvir (VEL) + NS5A inhibitor + 4, 5, 6 CTP ‐ A (DRV) voxilaprevir (VOX) NS3/4A protease inhibitor • Meds: Zepatier elbasvir (EBR) + NS5A inhibitor + 1, 4 √ CTP ‐ A – TDF/FTC/EFV: 1 tablet once ‐ daily grazoprevir (GZR) NS3/4A protease inhibitor – Omeprazole: 20mg once ‐ daily
Case #1 Recommended Question #1: Which ARVs have a major Treatment Options: drug ‐ drug interaction with SOF/VEL Tx ‐ Naïve, HCV Gt 1a, not cirrhotic (Epclusa) ? a. Efavirenz Regimens Dose Duration EBR/GZR * QD fixed ‐ dose combo EBR(50mg)/GZR (100mg) x12 weeks b. Darunavir/r GLE/PIB QD fixed ‐ dose combo GLE (300mg)/PIB (120mg) x8 weeks c. Tenofovir alafenamide SOF/LDV ** QD fixed ‐ dose combo SOF (400mg)/LDV (90mg) x12 weeks SOF/VEL QD fixed ‐ dose combo SOF (400mg)/VEL (100mg) x12 weeks d. Elvitegravir/c e. All of the above *If no baseline NS5A RAVs detected (for EBR) ** x8 weeks if HCV VL< 6 million, non ‐ black, HIV seronegative Mechanism of SOF/VEL SOF/VEL (Epclusa) ‐ ARV Interactions (Epclusa) Drug ‐ Drug Interactions Drug Class Drug Name Recommendation • SOF: substrate for P ‐ gp & BCRP VEL: substrate for P ‐ gp, BCRP, OATP, CYP3A4, NNRTIs RPV, DOR No dose adjustments needed CYP2C8, & CYP2B6 EFV, ETR Not recommended • Inducers of P ‐ gp, CYP2B6, CYP2C8, or CYP3A4 (e.g., PIs DRV/r/c, ATV/r/c, LPV/r No dose adjustments needed rifampin, St. John’s wort, EFV) ↓ plasma InSTI RAL No dose adjustments needed concentrations of SOF or VEL EVG/c No dose adjustments needed – Not recommended DTG No dose adjustments needed • VEL is inhibitor of P ‐ gp, BCRP, & OATP BIC No dose adjustments needed – Co ‐ administration of substrates of these transporters may ↑ exposure of such drugs N(t)RTI TDF/FTC or TAF/FTC No dose adjustments needed – Substrate of CYP3A4 ABC/3TC No dose adjustments needed
Case #1: Options 1. Change ART to non ‐ EFV ‐ containing regimen compatible with SOF/VEL (e.g., DTG ‐ , BIC ‐ , or RPV ‐ based) OR 2. Change DAA – EBR/GZR & GLE/PIB (substrates of CYP3A & P ‐ gp): incompatible with EFV – Consider SOF/LDV (Harvoni)x 12 weeks: compatible with EFV x 12 weeks: patient is African American, living with HIV, & HCV RNA>6 million https://www.hcvguidelines.org/unique ‐ populations/hiv ‐ hcv Question #2: What should you tell Case #1: OTC Interactions her about omeprazole? • 52 y/o woman, tx ‐ naïve, Gt 1a, no cirrhosis, CrCl=75 a. Nothing • Change ART to ABC/3TC/DTG b. Try to avoid acid blockers but, if you must, Monitor for side effects & continued HIV VL • take SOF/VEL with food & 4 hours before OMP suppression for 1 ‐ 2 months before starting DAAs c. Try to avoid acid blockers but, if you must, • 6 weeks later… take OMP 40mg once daily • Ready to start SOF/VEL (Epclusa) • You ask her about any OTCs & she reminds you d. Take famotidine or antacids instead of OMP, that she is taking omeprazole 20mg once daily given lack of interactions for reflux
VEL ‐ OMP Interaction Case #1: Acid Blockers and PPIs SOF/LDV SOF/VEL EBR/GZR GLE/PIB SOF/VEL/VOX • ↑ pH results in ↓ VEL solubility & ↓ VEL Antacids Separate by 4 hrs Separate by 4 hrs Separate by 4 hrs concentration H2RA Together or 12hrs Together or 12hrs Together or 12hrs apart; FAM 40mg BID apart; FAM 40mg BID apart; FAM 40mg BID • Try to avoid acid blockers altogether… PPIs Together with OMP With food, 4hrs Can use with OMP 20 20mg before OMP 20mg mg – PPIs: SOF/VEL with food & 4 hrs before PPI (at max No statistically significant difference in SVR12 between high & low PPI dose comparable to omeprazole 20mg) doses with GLE/PIB across genotypes; reasonable to avoid high dose PPI if possible – H2 ‐ RAs: Given simultaneously with or 12 hours apart from SOF/VEL at ≤ famotidine 40mg BID – Antacid: Separate by 4 hours Flamm S, et al. World Congress of Gastroenterology at ACG 2017; 2017; Orlando, FL. P1435. Case #1: Conclusion Case #2 • Pt’s ART changed to ABC/3TC/DTG A 45 year ‐ old male patient is being seen at the clinical pharmacy office to get started – Monitored for 6 weeks to ensure tolerating & HIV RNA suppressed on GLE/PIB (Mavyret) . • Starts SOF/VEL (Epclusa) & attains • HCV: Tx ‐ naïve, Gt1b, cirrhotic (Child ‐ Pugh Reminder: score A) SVR12 GLE/PIB can’t be used in • Meds: DRV/c/TAF/FTC, rosuvastatin – Stopped PPI when starting SOF/VEL & able decompensated cirrhosis (i.e., to control GERD with PRN famotidine Child ‐ Pugh B/C)
Case #2 Recommended Question #4: With which ARV is Treatment Options: GLE/PIB (Mavyret) compatible? Tx ‐ naïve, HCV Gt 1b, compensated cirrhosis a. ATV/r or DRV/r Regimens Dose Duration GLE/PIB QD fixed ‐ dose combo GLE (300mg)/PIB (120mg) x12 weeks b. ELV/c EBR/GZR QD fixed ‐ dose combo EBR(50mg)/GZR (100mg) x12 weeks c. EFV or ETR SOF/LDV QD fixed ‐ dose combo SOF (400mg)/LDV (90mg) x12 weeks d. RAL,DTG or BIC SOF/VEL QD fixed ‐ dose combo SOF (400mg)/VEL (100mg) x12 weeks e. All of the above Effect of Inhibitors on GLE/PIB (Mavyret) Question #4: With which ARV is GLE/PIB (Mavyret) compatible? a. ATV/r or DRV/r GLE/PIB ↑ ELV/c Cmax by 36%, AUC by 47%. b. ELV/c GLE Cmax & AUC 2.5 ‐ & 3.1 ‐ fold higher, c. EFV or ETR respectively, vs. GLE/PIB alone; PIB AUC 57% d. RAL,DTG or BIC higher. • GLE/PIB contraindicated with ATV/r/c No clinically significant • GLE/PIB may be okay with DRV/r & LPV/r but not interactions, but caution e. All of the above when using together. Very recommended due to lack of clinical data limited clinical data. • ELV/c leads to elevated GLE/PIB levels but may be used with caution
Case #2: Statin & HCV DAAs GLE/PIB (Mavyret) ‐ ARV Interactions • GLE/PIB (Mavyret) inhibit BCRP, P ‐ gp, OATP Drug Class Drug Name Recommendation – Rosuvastatin (substrate of BCRP & OATP) NNRTIs RPV, DOR No dose adjustments needed • Cmax ↑ 5.6x, AUC ↑ 2.2x EFV, ETR Not recommended • Do not exceed 10mg/d PIs ATV/r Not recommended – Pravastatin: reduced dose by 50% DRV/r, LPV/r Not recommended (yet) – Atorvastatin: do not co ‐ administer InSTI RAL, DTG No dose adjustments needed SOF/LDV SOF/VEL EBR/GZR GLE/PIB SOF/VEL/VOX Atorvastatin ND ND ≤ 20mg Lowest dose BIC No data; probably ok Pitavastatin ND ND Lowest dose ELV/c Caution Pravastatin ↓ dose by 50% ≤ 40mg N(t)RTI TDF, TAF No dose adjustments needed Rosuvastatin ≤ 10mg ≤ 10mg ≤ 10mg Simvastatin Lowest dose Lowest dose Side Note: Warfarin Side Note: Antiplatelet & DOACs • Updated SOF, SOF/LDV, SOF/VEL, SOF/VEL/VOX: • Limited data “Fluctuations in INR values may occur in patients • Limited ability to monitor patients on DOACS with receiving warfarin concomitant with HCV treatment... clinically available lab assays Frequent monitoring of INR values is recommended during treatment and post ‐ treatment...” SOF/LDV SOF/VEL EBR/GZR GLE/PIB SOF/VEL/VOX • Interaction more significant with ribavirin & PrOD Clopidogrel Caution Caution • Interaction usually results in ↓ INR, needing ↑ Warfarin Ticagrelor dose ( ≥ 15%) Dabigatran 2hr apart 2hr apart • Mechanism unclear but eradication of HCV improves liver Edoxaban ND ND ND ND function to increase clotting factor synthesis &/or Apixaban ND ND ND ND warfarin metabolism Rivaroxaban Caution Caution Caution Caution
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