HCV Pharmacology for All Clinicians

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1 HCV Pharmacology for All Clinicians Disclosure 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 2018 Resources AASLD/IDSA: EASL: practice guidelines Resources University of Liverpool: HEP ichart: uni.icharthep HCV drug drug interactions: druginteractions.org Toronto General Hospital s HCV drug drug interaction tables & news: Package inserts 1

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, &

2 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 2 new ARVs (bictegravir & doravirine): compatible with all DAAs. Refine DAA options based on interactions, prior AEs, & patient preferences populations/hiv hcv Quick DAA Recap Brand Generic MOA Gt HD Decomp. Cirrhosis EFV/ ETR PI/r /c Epclusa sofosbuvir (SOF) + NS5B inhibitor + 1, 2, 3, velpatasvir (VEL) NS5A inhibitor 4, 5, 6 Harvoni sofosbuvir (SOF) + NS5B inhibitor + 1, 4, 5, ledipasvir (LDV) NS5A inhibitor 6 Mavyret glecaprevir (GLE) + NS3/4A protease inhibitor + 1, 2, 3, pibrentasvir (PIB) NS5A inhibitor 4, 5, 6 CTP A ( ) Vosevi sofosbuvir (SOF) + NS5B inhibitor + velpatasvir (VEL) + NS5A inhibitor + voxilaprevir (VOX) NS3/4A protease inhibitor Zepatier elbasvir (EBR) + grazoprevir (GZR) NS5A inhibitor + NS3/4A protease inhibitor 1, 2, 3, 4, 5, 6 CTP A (DRV) 1, 4 CTP A Case #1 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), HCV VL= 10 million Labs: Normal liver function, CrCl= 75 Meds: TDF/FTC/EFV: 1 tablet once daily Omeprazole: 20mg once daily 2

3 Case #1 Recommended Treatment Options: 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 *If no baseline NS5A RAVs detected (for EBR) ** x8 weeks if HCV VL< 6 million, non black, HIV seronegative Question #1: Which ARVs have a major drug drug interaction with SOF/VEL (Epclusa)? a. Efavirenz b. Darunavir/r c. Tenofovir alafenamide d. Elvitegravir/c e. All of the above Mechanism of SOF/VEL (Epclusa) 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 exposure of such drugs Substrate of CYP3A4 SOF/VEL (Epclusa) ARV Interactions Drug Class Drug Name Recommendation NNRTIs RPV, DOR No dose adjustments needed EFV, ETR Not recommended PIs DRV/r/c, ATV/r/c, LPV/r No dose adjustments needed InSTI RAL No dose adjustments needed EVG/c No dose adjustments needed DTG No dose adjustments needed BIC No dose adjustments needed N(t)RTI TDF/FTC or TAF/FTC No dose adjustments needed ABC/3TC No dose adjustments needed 3

4 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 populations/hiv hcv Case #1: OTC Interactions 52 y/o woman, tx naïve, Gt 1a, no cirrhosis, CrCl=75 Change ART to ABC/3TC/DTG Monitor for side effects & continued HIV VL suppression for 1 2 months before starting DAAs 6 weeks later Ready to start SOF/VEL (Epclusa) 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. Nothing b. Try to avoid acid blockers but, if you must, take SOF/VEL with food & 4 hours before OMP c. Try to avoid acid blockers but, if you must, take OMP 40mg once daily d. Take famotidine or antacids instead of OMP, given lack of interactions 4

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

5 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: Acid Blockers and PPIs SOF/LDV SOF/VEL EBR/GZR GLE/PIB SOF/VEL/VOX Antacids Separate by 4 hrs Separate by 4 hrs Separate by 4 hrs H2RA Together or 12hrs apart; FAM 40mg BID Together or 12hrs apart; FAM 40mg BID Together or 12hrs apart; FAM 40mg BID PPIs Together with OMP 20mg With food, 4hrs before OMP 20mg Can use with OMP 20 mg No statistically significant difference in SVR12 between high & low PPI doses with GLE/PIB across genotypes; reasonable to avoid high dose PPI if possible Flamm S, et al. World Congress of Gastroenterology at ACG 2017; 2017; Orlando, FL. P1435. Case #1: Conclusion Pt s ART changed to ABC/3TC/DTG Monitored for 6 weeks to ensure tolerating & HIV RNA suppressed Starts SOF/VEL (Epclusa) & attains SVR12 Stopped PPI when starting SOF/VEL & able to control GERD with PRN famotidine 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 score A) Meds: DRV/c/TAF/FTC, rosuvastatin Reminder: GLE/PIB can t be used in decompensated cirrhosis (i.e., Child Pugh B/C) 5

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

6 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: With which ARV is GLE/PIB (Mavyret) compatible? a. ATV/r or DRV/r b. ELV/c c. EFV or ETR d. RAL,DTG or BIC e. All of the above Question #4: With which ARV is GLE/PIB (Mavyret) compatible? Effect of Inhibitors on GLE/PIB (Mavyret) a. ATV/r or DRV/r b. ELV/c c. EFV or ETR d. RAL,DTG or BIC e. All of the above GLE/PIB ELV/c Cmax by 36%, AUC by 47%. GLE Cmax & AUC 2.5 & 3.1 fold higher, respectively, vs. GLE/PIB alone; PIB AUC 57% higher. No clinically significant interactions, but caution when using together. Very limited clinical data. GLE/PIB contraindicated with ATV/r/c GLE/PIB may be okay with DRV/r & LPV/r but not recommended due to lack of clinical data ELV/c leads to elevated GLE/PIB levels but may be used with caution 6

7 GLE/PIB (Mavyret) ARV Interactions Drug Class Drug Name Recommendation NNRTIs RPV, DOR No dose adjustments needed EFV, ETR Not recommended PIs ATV/r Not recommended DRV/r, LPV/r Not recommended (yet) InSTI RAL, DTG No dose adjustments needed BIC No data; probably ok ELV/c Caution N(t)RTI TDF, TAF No dose adjustments needed Case #2: Statin & HCV DAAs GLE/PIB (Mavyret) inhibit BCRP, P gp, OATP Rosuvastatin (substrate of BCRP & OATP) Cmax 5.6x, AUC 2.2x Do not exceed 10mg/d Pravastatin: reduced dose by 50% Atorvastatin: do not co administer SOF/LDV SOF/VEL EBR/GZR GLE/PIB SOF/VEL/VOX Atorvastatin ND ND 20mg Lowest dose Pitavastatin ND ND Lowest dose Pravastatin dose by 50% 40mg Rosuvastatin 10mg 10mg 10mg Simvastatin Lowest dose Lowest dose 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 INR, needing Warfarin dose ( 15%) Mechanism unclear but eradication of HCV improves liver function to increase clotting factor synthesis &/or warfarin metabolism Side Note: Antiplatelet & DOACs Limited data Limited ability to monitor patients on DOACS with clinically available lab assays SOF/LDV SOF/VEL EBR/GZR GLE/PIB SOF/VEL/VOX Clopidogrel Caution Caution Ticagrelor Dabigatran 2hr apart 2hr apart Edoxaban ND ND ND ND Apixaban ND ND ND ND Rivaroxaban Caution Caution Caution Caution 7

Case #2: Options 45 y/o man starting GLE/PIB (Mavyret). Gt1b, cirrhotic, tx naïve; DRV/c/TAF/FTC, rosuvastatin. 1. Change ART Suggestions: DTG, BIC or RPV based or 2.

8 Case #2: Options 45 y/o man starting GLE/PIB (Mavyret). Gt1b, cirrhotic, tx naïve; DRV/c/TAF/FTC, rosuvastatin. 1. Change ART Suggestions: DTG, BIC or RPV based or 2. Change DAA SOF/LDV x12 weeks SOF/VEL x12 weeks Case #2: Conclusion Due to insurance coverage of GLE/PIB (Mavyret), we decide to change ART to DTG/ABC/3TC. Monitor HIV VL x1 2 months on new ART before starting DAAs Reduce rosuvastatin dose to 10mg. Start GLE/PIB. 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) Question #5: Which DAA agents are okay to use in those with egfr< 30 ml/min? 1. EBR/GZR (Zepatier) 2. GLE/PIB (Mavyret) 3. SOF/LDV (Harvoni) 4. SOF/VEL (Epclusa) 5. 1 & 2 6. All of the above 8

9 Case #3 Treatment Options: Renal Impairment CKD DAA No dose adjustment Duration 1 3 EBR/GZR QD EBR (50mg)/GZR (100mg) x12 weeks GLE/PIB QD GLE (300mg)/PIB (120mg) X8 16 weeks SOF/LDV QD SOF (400mg)/LDV (90mg) x12 weeks SOF/VEL QD SOF (400mg)/VEL (100mg) x12 weeks DCV + SOF QD DCV (60mg**) + SOF (400mg) x12 weeks SMV + SOF QD SMV (150mg) + SOF (400mg) x12 weeks SOF/VEL/VOX QD SOF (400mg)/VEL (100mg)/VOX (100mg) x12 weeks 4 5 EBR/GZR QD EBR (50mg)/GZR (100mg) x12 weeks GLE/PIB QD GLE (300mg)/PIB (120mg) X8 16 weeks Chronic Kidney Disease (CKD) stages: 1= normal (egfr >90 ml/min); 2= mild CKD (egfr ml/min); 3= moderate CKD (egfr ml/min) 4= severe CKD (egfr ml/min); 5= end stage CKD (egfr <15 ml/min) Case #3 General Options: Tx Naïve, Gt 3, no cirrhosis Regimens Dose Duration SOF/VEL QD fixed dose combo SOF x12 weeks (400mg)/VEL (100mg) GLE/PIB QD fixed dose combo GLE (300mg)/PIB (120mg) x8 weeks Case #3: Conclusion He initiates GLE/PIB (Mavyret) He does very well & has SVR posttreatment Important Points Only SOF/LDV (Harvoni) can be used with EFV or ETR. SOF/LDV & SOF/VEL (Epclusa) can be used with PI/r & EVG/c. EBR/GZR (Zepatier) & GLE/PIB (Mavyret) okay with PPIs. Pravastatin seems okay with most DAAs. EBR/GZR & GLE/PIB can be used in ESRD. SOF/VEL & SOF/LDV can be used in decompensated cirrhosis (treat in consultation with a liver specialist) GLE/PIB, EBR/GZR, & SOF/VEL/VOX (Vosevi) should not be used in those with Child Pugh B & C. 9

10 Acknowledgements Annie Luetkemeyer, MD Meg Newman, MD, FACP Diane V. Havlir, MD 10

Pharmacology for all HCV Clinicians

Pharmacology for all HCV Clinicians Disclosure I have nothing to disclose. Parya Saberi, PharmD, MAS Assistant Professor, UCSF Center for AIDS Prevention Studies Medical Management of HIV/AIDS and Hepatitis