12/8/2017 Disclosure Pharmacology for all • I have nothing to disclose. HCV Clinicians Parya Saberi, PharmD, MAS Assistant Professor, UCSF Center for AIDS Prevention Studies Medical Management of HIV/AIDS and Hepatitis December 2017 https://www.hcvguidelines.org/ Resources • AASLD/IDSA: www.hcvguidelines.org • EASL: www.easl.eu/medias/cpg/HCV ‐ recommendations/English ‐ report.pdf 1
12/8/2017 Selecting & Refining HCV Treatment Options Resources • University of Liverpool: Patients being considered for – HEP iChart: play.google.com/store/apps HCV therapy – HCV drug ‐ drug interactions: www.hep ‐ druginteractions.org Determine all possible DAA options based on genotype, presence of – HIV drug ‐ drug interactions: www.hiv ‐ cirrhosis, treatment ‐ naïve or ‐ experienced, & drug resistance druginteractions.org Review all prescription & OTC meds • Toronto General Hospital’s HCV drug ‐ drug & herbal supplements interaction tables & news: www.hcvdruginfo.ca/ • Indiana University’s CYP drug interaction table: Screen for interactions using resources & package inserts Medicine.iupui.edu/clinpharm/ddis • Package inserts Refine DAA options based on interactions, prior AEs, & patient preferences Case #1 Quick DAA Recap Brand Generic MOA Gt HD Decomp. EFV/ETR PI/r A 52 year ‐ old African American woman comes Cirrhosis /c 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, √ ( √ ) cirrhosis (APRI= 0.3) pibrentasvir (PIB) NS5A inhibitor 4, 5, 6 Vosevi sofosbuvir (SOF) + NS5B inhibitor + 1, 2, 3, • Labs: Normal liver function, CrCl= 63 ( √ ) velpatasvir (VEL) + NS5A inhibitor + 4, 5, 6 voxilaprevir (VOX) NS3/4A protease inhibitor • Meds: Zepatier elbasvir (EBR) + NS5A inhibitor + 1, 4 √ – TDF/FTC/EFV: 1 tablet once ‐ daily grazoprevir (GZR) NS3/4A protease inhibitor – Omeprazole: 20mg once ‐ daily 2
12/8/2017 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 a. Efavirenz Regimens Dose Duration b. Darunavir/r EBR/GZR* QD fixed ‐ dose combo EBR(50mg)/GZR (100mg) x12 weeks 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 d. Elvitegravir/c SOF/VEL QD fixed ‐ dose combo SOF (400mg)/VEL (100mg) x12 weeks e. All of the above *If no baseline NS5A RAVs detected (for EBR) Mechanism of SOF/VEL Mechanism of SOF/VEL Drug ‐ Drug Interactions Drug ‐ Drug Interactions • SOF: substrate for P ‐ gp & BCRP • SOF: substrate for P ‐ gp & BCRP VEL: substrate for P ‐ gp, BCRP, OATP, CYP3A4, VEL: substrate for P ‐ gp, BCRP, OATP, CYP3A4, CYP2C8, & CYP2B6 CYP2C8, & CYP2B6 • Inducers of P ‐ gp, CYP2B6, CYP2C8, or CYP3A4 (e.g., Organic anion Cytochrome P450 P ‐ glycoprotein : Breast Cancer rifampin, St. John’s wort, EFV) ↓ plasma transporting Enzymes: >50 efflux enzyme Resistance Protein: polypeptide: concentrations of SOF or VEL enzymes essential that “pushes” expressed in small involved in for metabolism of drugs out of GI intestine, liver, secretion or – Not recommended 2/3 of meds blood stream kidneys, & blood ‐ reabsorption of cleared by • VEL is inhibitor of P ‐ gp, BCRP, & OATP back into GI brain barrier & drugs (organic metabolism. lumen; also in plays important anions); across cell – Co ‐ administration of substrates of these transporters Primary cause of liver, kidneys, & role in drug membrane in drug ‐ drug & drug ‐ may increase exposure of such drugs blood ‐ brain disposition & tissue kidneys, brain, & food interactions barrier protection liver 3
12/8/2017 VEL ‐ EFV Interaction Summary: SOF/VEL ‐ ARV Interactions • VEL: substrate of CYP3A4 • VEL + EFV: ~50% decrease in VEL exposure Drug Class Drug Name Recommendation NNRTIs RPV No dose adjustments needed EFV, ETR Not recommended PIs DRV/r, ATV/r, LPV/r No dose adjustments needed InSTI RAL No dose adjustments needed EVG/c/FTC/TDF No dose adjustments needed DTG No dose adjustments needed N(t)RTI TDF/FTC No dose adjustments needed ABC/3TC No dose adjustments needed Mogalian E, Luetkemeyer A, et al. AIDS 2016; Durban, South Africa. Question #2: What should you tell Case #1: OTC Interactions her about omeprazole? 52 y/o woman, tx ‐ naïve, Gt 1a, no cirrhosis, CrCl=63, a. Nothing on TDF/FTC/EFV b. Try to avoid acid blockers but, if you must, You ask her about any OTCs & she take SOF/VEL with food & 4 hours before OMP reminds you that she is taking c. Try to avoid acid blockers but, if you must, omeprazole 20mg once daily for take OMP 40mg once daily reflux. d. Take famotidine or antacids instead of OMP, given lack of interactions 4
12/8/2017 VEL ‐ OMP Interaction Case #1: Options • ↑ pH results in ↓ VEL solubility & ↓ VEL 1. Change ART to non ‐ EFV ‐ containing concentration regimen (e.g., DTG) • Try to avoid acid blockers altogether… – She tried ABC/3TC/DTG before & had severe insomnia, so she refuses any ART change – PPIs: SOF/VEL with food & 4 hrs before PPI (at max OR dose comparable to omeprazole 20mg) 2. Change DAA – H2 ‐ RAs: Given simultaneously with or 12 hours apart from SOF/VEL at ≤ famotidine 40mg BID – EBR/GZR & GLE/PIB (substrates of CYP3A & – Antacid: Separate by 4 hours P ‐ gp): incompatible with EFV – Decide to try SOF/LDV ( Harvoni ) Mechanism of SOF/LDV Question #3: Which ARV regimens Drug ‐ Drug Interactions have drug ‐ drug interactions with SOF/LDV? • SOF/LDV: substrates of drug transporters P ‐ gp & BCRP a. DTG/ABC/3TC • P ‐ gp inducers (e.g., rifampin, St. John’s wort): b. Any TDF ‐ containing regimens may ↓ SOF/LDV plasma concentra � ons – not recommended c. Any HIV PI/r ‐ based regimens • Clinically significant interactions mediated by d. Any TAF ‐ containing regimens CYP450 or UGT1A1 enzymes are not expected e. Any NNRTI ‐ based regimens 5
12/8/2017 TDF & SOF/LDV TAF & SOF/LDV Possible mechanism: • – LDV inhibits efflux transporters (P ‐ gp & BCRP) leading to ↑ TFV exposure SOF/LDV does not significantly impact TAF or TFV PK – In vitro, SOF/LDV increase TFV absorption ↑ 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. Custodio JM, et al. IDSA/IDWeek 2015; San Diego, CA. Side Note: SOF/VEL + TDF or TAF Summary: SOF/LDV ‐ ARV Interactions Drug Class Drug Name Recommendation NNRTIs EFV, ETR, NVP, RPV No dose adjustments needed PIs ATV/r, DRV/r, LPV/r No dose adjustments needed TPV Not recommended InSTI ELV/c 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 concentra � ons. Consider alterna � ve therapy; or LPV/r) monitor for TDF ‐ associated renal dysfunction • SOF/VEL + TDF: increased TFV AUC by 20 ‐ 81% TAF No dose adjustments needed – Recommend: monitor renal function or change TDF 3TC, ABC, FTC, ZDV No dose adjustments needed CCR5 Inhibitor MVC No data • SOF/VEL + TAF: no clinically significant impact on TFV Only DAA compatible with EFV (& likely with ETR) Mogalian E, Luetkemeyer A, et al. AIDS 2016; Durban, South Africa. 6
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