Community Pharmacy Considerations for HIV & HCV Therapy Larry Pineda, PharmD, PhC, BCPS, AAHIVP Visiting Assistant Professor UNM College of Pharmacy

Conflicts of Interest Disclosure No conflicts of interest

Learning Objectives – Pharmacist List the DHHS recommended HIV antiretroviral regimens Describe current HCV direct-acting antivirals Discuss the importance of adherence counseling for HIV antiretrovirals and HCV direct-acting antivirals Recognize common prescription and nonprescription drug interactions with HIV antiretrovirals and HCV direct-acting antivirals

Learning Objectives – Pharm Tech Identify common HIV antiretrovirals and HCV direct-acting antivirals State the minimum number of antiretroviral drugs in an appropriate HIV antiretroviral regimen Understand the importance of adherence counseling for HIV antiretrovirals and HCV direct-acting antivirals Describe the impact of drug-drug interactions with HIV and HCV medications 

HIV therapy considerations

HIV Antiretroviral Therapy Inhibit viral replication HIV life cycle Antiretroviral drugs target key steps in replication https://www.youtube.com/watch?v=odRyv7V8LAE Figure: http://collections.infocollections.org/whocountry/en/d/Jh4325e/7.html

HIV Antiretroviral Therapy Entry inhibitors Attachment Selzentry (maraviroc) Fusion Fuzeon (enfuvirtide) Reverse transcriptase inhibitors Nucleoside Truvada (tenofovir disoproxil (TDF)/emtricitabine) Descovy (tenofovir alafenomide (TAF)/emtricitabine) Epzicom (abacavir/lamivudine) Non-nucleoside Sustiva (efavirenz) Edurant (rilpivirine)

HIV Antiretroviral Therapy Integrase strand transfer inhibitors Isentress (raltegravir) Vitekta (elvitegravir) Always with cobicistat (booster) Tivicay (dolutegravir) Protease inhibitors Prezista (darunavir) Reyataz (atazanavir) Norvir (ritonavir)

DHHS Recommended Agents Updated July 2016 Available at: https://aidsinfo.nih.gov/guidelines 5 recommended HAART regimens: 4 integrase-based regimens 1 protease inhibitor-based regimen

Integrase-Based Regimens Single tablet Triumeq (dolutegravir/abacavir/lamivudine) Genvoya (elvitegravir/cobicistat/TAF/emtricitabine) or Stribild (elvitegravir/cobicistat/TDF/emtricitabine) Two tablet Dolutegravir + TDF/emtricitabine or TAF/emtricitabine Raltegravir* + TDF/emtricitabine or TAF/emtricitabine *Twice daily dosing https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0/

Protease Inhibitor-Based Regimen Darunavir/ritonavir + TDF/emtricitabine or TAF/emtricitabine Atazanavir based regimens moved to alternative Non-nucleoside reverse transcriptase inhibitor based regimens on alternative list Entry inhibitors typically reserved for patients with resistance to recommended agents https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0/

What is the minimum number of antiretroviral agents that should be included in an ideal HIV treatment regimen? https://www.polleverywhere.com/multiple_choice_polls/pE0IUz9kkzCWEkA

HAART Highly Active Anti-Retroviral Therapy 3 active antiretroviral drugs 2 nucleoside reverse transcriptase inhibitors Plus 3rd active agent: Integrase strand transfer inhibitor Non-nucleoside reverse transcriptase inhibitor Protease inhibitor with pharmacokinetic enhancer (cobicistat, ritonavir) Goal: undetectable HIV viral load Adherence critical for success https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0/

What is the percentage of adherence to HAART needed for optimal virologic supression? https://www.polleverywhere.com/multiple_choice_polls/leQU8iVxVcr7F1U

Virologic Impact of Adherence Adherence to a regimen is essential to optimize therapeutic outcomes and is important in terms of evolution of resistance In order to achieve optimal suppression (or virologic response) it requires the patient to have almost perfect adherence Microelectronic monitoring system Patterson DL et al. Ann Intern Med. 2000;133:21-30

Virologic Impact of Adherence Adherence was estimated using pharmacy refill data in 886 treatment-naive individuals in British Columbia followed prospectively for a median of 19 months after starting ART. Of the 502 individuals at the 95-100% adherence rate, 84% achieved plasma viral loads <500 copies/mL, whereas only 64% of the 64 people at the 90% to <95% adherence rate achieved this level of suppression (p = 0.001). Thus, while adherence measurement with MEMS caps and pharmacy refill data may not be strictly comparable, this study also found that near-perfect levels of adherence are required for reliable viral suppression. Low-Beer S, Yip B, O'Shaughnessy MV, Hogg RS, Montaner JS. Adherence to triple therapy and viral load response. J Acquir Immune Defic Syndr 2000; 23:360-1. Low-Beer S et al. J Acquir Immune Defic Syndr. 2000; 23:360-1

Adherence Considerations Do not assume prescriber has provided education Monitor refill history Offer adherence devices Pill box Blister packaging Reminders (alarms, logs, apps, visual med calendar) Recognize “outdated” regimens Screen for polypharmacy Avoid treatment gaps

Antiretroviral Considerations Do not dispense partial regimens Question regimens with < 3 agents Truvada for preexposure prophylaxis (PrEP) and nuc-sparing regimens are exception Recognize “outdated” regimens Quality of life Assist with prior authorizations Facsimile response monitoring Drug interactions Alert fatigue

Drug Interactions New agents have less drug interactions Are not void of interactions Keep in mind OTC/supplements/herbals Bookmark key resources Don’t assume provider has checked

Integrase Inhibitors Low drug interactions Polyvalent cations Ca++, Fe++, Mg++, Zn++, Al+++ Chelate integrase inhibitors Does not include food products Maalox, Tums, multivitamins Administer 2 hours before or 6 hours after taking products containing polyvalent cations http://www.hiv-druginteractions.org/

St. John’s Wort Induction of UGT1A1 and CYP3A4 Decreased dolutegravir exposure Decreased elvitegravir/cobicistat concentrations Potentially decreased raltegravir exposure Decreased darunavir concentrations http://www.hiv-druginteractions.org/

Herbals Induce CYP3A4 Inhibit CYP3A4 Garlic supplements Ginkgo biloba Can induce CYP3A4 and/or P-gp Inconsistent data on allicin containing formulations Does not apply to dietary exposure Dolutegravir, ritonavir and cobicistat Ginkgo biloba Inhibit CYP3A4 Grapefruit, goldenseal, ginseng Grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4)

Pharmaceutical Boosters Ritonavir and cobicistat Inhibit CYP3A4, others vary Anticoagulants Warfarin (R enantiomer) Monitor INR Apixaban, dabigatran, rivaroxaban, ticagrelor Avoid concomitant use Anticonvulsants Carbamazepine, phenobarbital, phenytoin Decreases dolutegravir – UGT1A1, CYP3A4 induction Alternative – levetiracetam (Keppra) Warfarin is a mixture of enantiomers which are metabolised by different cytochromes. R-warfarin is primarily metabolised by CYP1A2 and 3A4. S-warfarin (more potent) is metabolised by CYP2C9. Cobicistat could potentially increase warfarin concentrations by inhibition of CYP3A4. Monitor INR during coadministration and for the first weeks after stopping cobicistat. Ritonavir induces CYP2B6, CYP2C9 instead of inhibit http://www.hiv-druginteractions.org/

Corticosteroids Interaction with both ritonavir and cobicistat Cushing’s syndrome, adrenal suppression Intranasal Fluticasone (Flonase)* Triamcinolone (Nasacort)* Budesonide (Rhinocort)* Inhaled Fluticasone/salmeterol (Advair) Budesonide/formoterol (Symbicort) Alternative Beclomethasone (QVAR, QNASL) *available over the counter http://www.hiv-druginteractions.org/

Serotonin Reuptake Inhibitor (SSRI) Paroxetine, fluoxetine, citalopram Metabolized by CYP2D6 Ritonavir inhibits metabolism Increased SSRI exposure Sertraline Metabolized by CYP2B6 Ritonavir induces metabolism Decreased SSRI exposure http://www.hiv-druginteractions.org/

Drug Interaction Resource Not all inclusive…resource http://www.hiv-druginteractions.org/ Also available as an app: hivichart

Hcv therapy considerations

Abbreviations SVR: sustained virologic response IFN: interferon RBV: ribavirin Peg: pegylated BOC: boceprevir TPV: telaprevir SMV: simeprevir SOF: sofosbuvir PrOD: paritaprevir/ritonavir + ombitasvir + dasabuvir PrO: paritaprevir/ritonavir + ombitasvir DCV: daclatasvir EBR/GZR: elbasvir/grazoprevir LDV/SOF: ledipasvir/sofosbuvir SOF/VEL: sofosbuvir/ velpatasvir Reference

HCV Treatment Historically complex therapy Gastroenterology, hepatology, infectious diseases Severe side effects, injectable Low cure rates Advent of new direct acting all oral medications has simplified management Less side effects Shorter duration Higher cure rates Goal of treatment is SVR New agents highly effective SVR rates >90%

Evolution of HCV Treatment 2014 2016 LDV/SOF DCV+ SOF EBR/ GZR SOF/ VEL BOC and TPV 2013 PrOD SOF SMV >90 >90 >90 >90 >90 100 89+ 80+ PegIFN 2011 80 RBV 2001 Standard IFN 70+ 1998 60 55 SVR (%) 1991 42 39 40 34 Focus on how many are approved recently Treatment for HCV has evolved dramatically. On the y-axis, you see here the % of patients expected to achieve cure-defined as sustained virologic response, or SVR. On the x-axis are the various HCV therapies. For nearly two decades the standard of care was an interferon based regimen for 6-12 months, combined with ribavirin resulting in, at best, 50% of patients achieving cure with a year’s worth of treatment. In 2011, the first generation of direct-acting antivirals were approved- boceprevir and telaprevir. Although these agents markedly improved SVR rates, in addition to the toxicities and laboratory abnormalities of interferon, these early agents were also plagued by substantial side effects and a high pill burden. By 2014, we entered a new era of therapy hallmarked by the ability to treat with an all-oral regiment, sparing the need for interferon, with few side effects and, more importantly high cure rates with abbreviated courses of treatment. In the last year, in addition to simeprevir, sofosbuvir, ledipasvir-sofosbuvir combination tablet, and paritaprevir boosted with ritonavir, ombitasvir, and dasabuvir, daclatasvir was approved in combination with sofosbuvir and most recently, in Jan 2015, the combination of elbasvir/grazoprevir was approved in the US. 20 16 6 PegIFN/ RBV/ BOC or TPV 6-12 mos IFN 12 mos IFN/RBV 6 mos IFN/RBV 12 mos PegIFN 12 mos PegIFN RBV 12 mos PegIFN/ RBV/ SMV 24-48 wks PegIFN/ RBV/ SOF 12-24 wks LDV/ SOF 8-12 wks PrOD + RBV 12-24 wks SOF + DCV 12 wks IFN 6 mos EBR/ GZR 12-16 wks SOF/ VEL 12 wks Slide courtesy Paulina Deming, PharmD, PhC

Key Differences in HCV Therapy PegIFN Based Therapy Direct Acting Antivirals Injections Significant laboratory abnormalities Pancytopenias Ribavirin  hemolytic anemia Substantial side effect profile Limited use in advanced liver disease Limited drug interaction potential Low SVR All oral Limited laboratory abnormalities Ribavirin  hemolytic anemia Low side effect profile Variable drug interaction potential Variable use in advanced liver disease High SVR Emerging concerns for HCV resistance

HCV Treatment Highlights Guided by HCV genotype G1a most common in US Finite duration of treatment Typically ~12 weeks Adherence vital for treatment success Retreatment Lower SVR rates Longer duration, + ribavirin Cost of treatment high http://www.hepatitisc.uw.edu/ http://www.hcvguidelines.org/

Cost of HCV Treatment http://www.hepatitisc.uw.edu

HCV Drug Targets Ribavirin Boceprevir (BOC) Telaprevir (TVR) Core E1 E2 P7 NS2 NS3 4A NS4B NS5A NS5B 5’UTR 3’UTR NS3 Protease Inhibitors NS5A Replication Complex Inhibitors NS5B Polymerase (Nucleotide) Inhibitors NS5B Polymerase (Non-nucleotide) Inhibitors Ribavirin Boceprevir (BOC) Telaprevir (TVR) Simeprevir (SMV) Paritaprevir (PTV) Grazoprevir (GRZ) Daclatasvir (DCV) Ledipasvir (LDV) Ombitasvir (OMV) Elbasvir (EBR) Velpatasvir (VEL) Sofosbuvir (SOF) Dasabuvir (DSV) Pulled from market This diagram shows the proteins encoded by HCV genome, and where DAAs target their activity against the virus Slide courtesy Monique, Dodd, PharmD, MLS(ASCP)

HCV Direct Acting Antivirals (DAAs) Target NS3/4A: Protease Inhibitors (-previr) NS5A: Replication Complex Inhibitors (-asvir) NS5B: Polymerase Inhibitors (-buvir) DAA Boceprevir* Telaprevir* Simeprevir Paritaprevir Grazoprevir Ledipasvir Ombitasvir Daclatasvir Elbasvir Velpatasvir Nucleotide: Sofosbuvir Non-nucleoside: Dasabuvir Currently available DAAs fall into 1 of 3 categories * Pulled from market

Treatment Resources Joint guidelines of the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) Updated frequently – check online for most current version of guidelines Available at: http://www.hcvguidelines.org/ Hepatitis C Online (Univ. of Washington) http://www.hepatitisc.uw.edu/ HCV medication information, calculators, guidance HCV course (modules)

Pharmacy Considerations High cost – specialty pharmacy High copays, patient assistance networks Avoid treatment gaps Time it takes to order medication Counseling: Adverse effects Adherence Despite short, finite duration Drug interactions

Side Effect Profile of DAAs Most commonly reported side effects: Headache Fatigue Nausea Most common laboratory abnormalities: ALT elevations with PrOD and ethinyl-estradiol use; ALT elevations with EBR/GZR Anemia with concomitant use of ribavirin Ribavirin causes hemolytic anemia Overall well tolerated http://www.hepatitisc.uw.edu/

What is the percentage of adherence to HCV DAAs needed for optimal outcome? https://www.polleverywhere.com/multiple_choice_polls/PT6sZBp5K4GWYRx

HCV Therapy Adherence No published literature on DAA adherence correlation to SVR Optimal adherence yet to be determined Recommend 100% adherent to DAAs Adherence assessment and counseling at all healthcare encounters

Drug Interaction Concerns for DAAs Overall have low potential for drug-drug interactions Amiodarone with sofosbuvir and other DAA Serious symptomatic bradycardia Potential for other drugs to lower DAA concentrations Strong CYP3A inducers (e.g. carbamazepine, oxcarbazepine, phenobarbital, phenytoin) Strong intestinal P-glycoprotein inducers (e.g. rifampin) St. John’s wort (avoid all herbals/supplements) Statins Interactions vary by DAA and statin www.hep-druginteractions.org

Acid Suppressive Therapy Ledipasvir and velpatasvir solubility decreases with increases in pH Requires acidity for absorption – greatest concern with velpatasvir Antacids Separate administration by 4 hours H2RAs Administered simultaneously with or 12 hours apart PPIs Can be administered simultaneously if medically necessary www.hep-druginteractions.org

Drug Interaction Resource Liverpool – England so some spelling is different (less is more sometimes when searching for meds) acyclovir for example, spelled aciclovir www.hep-druginteractions.org www.hep-druginteractions.org Also available as an app: hepichart

Patient Case DD is a 48 year old HIV+ male with HCV coinfection. His provider has prescribed Harvoni (ledipasvir/sofosbuvir) x 12 weeks. Medications: famotidine prn heartburn, Tums prn heartburn, dolutegravir, emtricitabine/TDF, acyclovir No known drug allergies

What relevant drug interactions would you notify prescriber about? https://www.polleverywhere.com/free_text_polls/UJ4Nq2cz1rwtIVb

Questions/considerations?