ACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals

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2 Antiretroviral Medications: What you need to know Jason J. Schafer, PharmD, MPH, BCPS, AAHIVP Associate Professor, Department of Pharmacy Practice Jefferson College of Pharmacy, Thomas Jefferson University

3 Learning Objectives Upon completion of this presentation, learners should be better able to: Review the life cycle of HIV and the targets for antiretroviral therapy Describe the mechanisms of action of antiretroviral medications for the treatment of HIV infection Identify factors that influence the choice of antiretroviral therapy in treatment naïve patients

4 Faculty and Planning Committee Disclosures Please consult your program book. I have received grant funding from Merck Pharmaceuticals for investigator initiated research There will be no off-label/investigational uses discussed in this presentation.

5 What Antiretroviral Therapy to Start A Moving Target DHHS Guidelines Recommended Regimens Protease inhibitor based Darunavir + ritonavir + emtricitabine + TDF Atazanavir + ritonavir + emtricitabine + TDF Integrase inhibitor based Raltegravir + emtricitabine + TDF NNRTI based: Efavirenz + emtricitabine + TDF DHHS: Department of Health and Human Services, TDF: tenofovir disoproxil fumarate, NNRTI: nonnucleoside reverse transcriptase inhibitor

6 What Antiretroviral Therapy to Start A Moving Target DHHS Guidelines Recommended Regimens Protease inhibitor based Integrase inhibitor based Darunavir + ritonavir + emtricitabine + TDF Raltegravir + emtricitabine + TDF Elvitegravir + cobicistat + emtricitabine + TDF or TAF Dolutegravir + emtricitabine + TDF Dolutegravir + abacavir + lamivudine DHHS: Department of Health and Human Services, TDF: tenofovir disoproxil fumarate, TAF: tenofovir alafenamide

7 What Antiretroviral Therapy to Start A Moving Target DHHS Guidelines Recommended Regimens Raltegravir + emtricitabine a + TDF or TAF b Integrase inhibitor based Elvitegravir + cobicistat + emtricitabine a + TDF or TAF b Dolutegravir + emtricitabine a + TDF or TAF b Dolutegravir + abacavir + lamivudine a Bictegravir + emtricitabine a + TAF b DHHS: Department of Health and Human Services, TDF: tenofovir disoproxil fumarate, TAF: tenofovir alafenamide a Lamivudine may substitute for emtricitabine or vice versa. b Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are two forms of tenofovir approved by the Food and Drug Administration. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs. US DHHS. Guidelines for Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents Accessed March, 2018.

HIV Life Cycle and Targets 1. CD4 receptor 2. CCR5 co-receptor 3. Glycoprotein 41 4.

8 HIV Life Cycle and Targets 1. CD4 receptor 2. CCR5 co-receptor 3. Glycoprotein Reverse transcriptase enzyme Nucleos(t)ide reverse transcriptase inhibitors Non-nucleoside reverse transcriptase inhibitors 5. Integrase enzyme Protease enzyme

9 Inhibiting Viral Entry CD4 Receptor Antagonists, Co-Receptor Antagonists and Fusion Inhibitors CD4 Receptor antagonist Image adapted from: Moore JP, et al. Proc Natl Acad Sci U S A. 2003;100:

10 Inhibiting Viral Entry CD4 Receptor Antagonists, Co-Receptor Antagonists and Fusion Inhibitors Enfuvirtide GP41 antagonist, subcutaneous injection Not recommended as initial therapy Maraviroc CCR5 antagonist, tropism test required Not recommended as initial therapy Brand Name Generic Name Approval Date Fuzeon Enfuvirtide 2003 Selzentry Maraviroc 2007 Trogarzo Ibalizumab 2018 Ibalizumab Humanized monoclonal antibody Binds to the extracellular domain of the CD4+ receptor Heavily treatment experienced patients

Blocking Reverse Transcription Nucleoside Reverse Transcriptase Inhibitors Mechanism of action Structural analogues of nucleoside bases Competitively

11 Blocking Reverse Transcription Nucleoside Reverse Transcriptase Inhibitors Mechanism of action Structural analogues of nucleoside bases Competitively bind to reverse transcriptase enzyme Incorporate into DNA chain and terminate DNA synthesis Image adapted from Clavel F. N Engl J Med 2004;350:

12 Blocking Reverse Transcription Nucleoside Reverse Transcriptase Inhibitors ABC/3TC, TAF/FTC, and TDF/FTC are the recommended NRTI combinations for use as initial therapy. Recommendations are based on the potency, durability, toxicity, and convenience. Safety is among the factors to consider when choosing between these drugs. Brand Name Generic Name Approval Date Epivir Lamivudine (3TC) 1995 Ziagen Abacavir (ABC) 1998 Epzicom Abacavir/lamivudine 2004 Viread Tenofovir disoproxil fumarate (TDF) 2001 Vemlidy Tenofovir alafenamide (TAF) 2016 Emtriva Emtricitabine (FTC) 2003 Truvada TDF/emtricitabine 2004 Descovy TAF/emtricitabine 2016

Blocking Reverse Transcription Non-Nucleoside Reverse Transcriptase Inhibitors Mechanism of action Non-competitive binding to reverse transcriptase

13 Blocking Reverse Transcription Non-Nucleoside Reverse Transcriptase Inhibitors Mechanism of action Non-competitive binding to reverse transcriptase Not analogues of nucleoside bases Bind adjacent to the catalytic site of enzyme Efavirenz Image adapted from Clavel F. N Engl J Med 2004;350:

14 Blocking Reverse Transcription Non-Nucleoside Reverse Transcriptase Inhibitors Currently recommended as initial regimens only in certain clinical situations for the following reasons: Low genetic barrier for resistance; Efavirenz is less well tolerated than the recommended regimens; and Virologic failure is more common with rilpivirine with high pretreatment viral loads (>100,000 copies/ml) or low CD4 counts (<200 cells/mm3) Brand Name Generic Name *Single tablet regimens Approval Date Sustiva Efavirenz 1998 Atripla* Efavirenz, emtricitabine, TDF 2006 Edurant Rilpivirine 2011 Intelence Etravirine 2012 Complera* Rilpivirine, emtricitabine, TDF 2012 Odefsey* Rilpivirine, emtricitabine, TAF 2016

15 Blocking Viral DNA Integration Integrase Inhibitors Mechanism of action: Inhibit insertion of HIV DNA into human DNA following reverse transcription

16 Blocking Viral DNA Integration Integrase Inhibitors Recommended as initial treatment for most people with HIV Agents are generally well tolerated Reports of insomnia in some patients Rare reports of depression and suicidal ideation, primarily in patients with a history of psychiatric illnesses Often better tolerated than comparator agents in clinical trials Brand Name Generic Name Approval Date Isentress Raltegravir 2007 Stribild* Elvitegravir, cobicistat, TAF, and emtricitabine 2012 Tivicay Dolutegravir 2013 Triumeq* Dolutegravir, abacavir, lamivudine 2014 Genvoya* Elvitegravir, cobicistat, TAF, and emtricitabine 2015 Biktarvy* Bictegravir, TAF and emtricitabine 2018 *Single tablet regimens

17 Blocking The Production of Viral Proteins Protease Inhibitors Mechanism of Action Bind to protease enzyme prevent cleavage of HIV polyproteins 1. The production of viral polypeptides from mrna 2. Cleavage of polypeptides to form HIV proteins

18 Blocking The Production of Viral Proteins Protease Inhibitors Potent and durable in naive patients, with a high barrier to resistance Useful for patients at risk for poor adherence Less well tolerated than integrase inhibitors in clinical trials Brand Name Generic Name Approval Date Norvir Ritonavir 1996 Kaletra Lopinavir/ritonavir 2000 Reyataz Atazanavir 2003 Prezista Darunavir 2006 Evotaz Atazanavir/cobicistat 2015 Prezcobix Darunavir/cobicistat 2015 All inhibit CYP3A4, which may lead to significant drug-drug interactions

19 What Antiretroviral Therapy to Start How to Choose? DHHS Guidelines Recommended Regimens Raltegravir + emtricitabine a + TDF or TAF b Integrase inhibitor based Elvitegravir + cobicistat + emtricitabine a + TDF or TAF b Dolutegravir + emtricitabine a + TDF or TAF b Dolutegravir + abacavir + lamivudine a Bictegravir + emtricitabine a + TAF b DHHS: Department of Health and Human Services, TDF: tenofovir disoproxil fumarate, TAF: tenofovir alafenamide a Lamivudine may substitute for emtricitabine or vice versa. b Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are two forms of tenofovir approved by the Food and Drug Administration. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs. US DHHS. Guidelines for Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents Accessed March, 2018.

20 What Antiretroviral Therapy to Start Efficacy Safety/Tolerability Convenience/Pill Size Drug-Drug Interactions Comorbidities/Co-infections Resistance/Resistance Barrier Pregnancy Influential Factors for the Treatment Naïve Patient

21 Audience Response Question 1: Why are integrase inhibitor based regimens recommended ahead of comparators? A. They more often lead to virologic suppression B. They have fewer drug interactions C. They are comparably effective, but have better tolerability D. They have a higher barrier to HIV resistance

23 Antiretroviral Therapy Selection Integrase Inhibitors and the Comparators Efficacy and Tolerability Study IntegraseAgent Comparator(s) Follow-up (Wks) Efficacy STARTMRK Raltegravir Efavirenz 192 Weeks Raltegravir superior to efavirenz ACTG 5257 Raltegravir Darunavir/ritonavir Atazanavir/ritonavir 96 Weeks Raltegravir superior to darunavir/ritonavir Raltegravir superior to atazanavir/ritonavir GS-102 Elvitegravir/cobicistat Efavirenz 144 Weeks Elvitegravir non-inferior to efavirenz GS-103 Elvitegravir/cobicistat Atazanavir/ritonavir 144 Weeks Elvitegravir non-inferior to atazanavir WAVES Elvitegravir/cobicistat Atazanavir/ritonavir 48 Weeks Elvitegravir superior to atazanavir/ritonavir SINGLE Dolutegravir Efavirenz 48 Weeks Dolutegravir superior to efavirenz FLAMINGO Dolutegravir Darunavir/ritonavir 48 Weeks Dolutegravir superior to darunavir/ritonavir GS-US Bictegravir Dolutegravir 48 Weeks Bictegravir non-inferior to dolutegravir GS-US Bictegravir Dolutegravir 48 Weeks Bictegravir non-inferior to dolutegravir

24 Choosing Between The Integrase Inhibitors

25 Audience Response Question 2: Which of the following medications has a significant interaction with all integrase inhibitors? A. Omeprazole B. Simvastatin C. Metformin D. Multivitamins

27 Antiretroviral Therapy Selection Choosing Between The Integrase Inhibitors Drug-Drug Interactions Absorption INSTIs are not negatively impacted by the concurrent use of proton pump inhibitors or H2-blockers INSTs are negatively impacted by divalent and trivalent cations in antacids and multivitamins through chelation interactions Drug Raltegravir Elvitegravir Dolutegravir Bictegravair Recommendation with Al, Mg Containing Antacids Do not co-administer with Al-Mg antacids Separate by 2 hours Administer DOL 2 hours prior or 6 hours after antacid Separate by 2 hours Metabolism Raltegravir has the least interactions Dolutegravir and bictegravir have some CYP3A4 metabolism and therefore few drug interactions Elvitegravir has many interactions due to CYP3A4 metabolism and cobicistat boosting Drug Substrate Inhibits Induces Raltegravir UGT Elvitegravir/Cobi 3A4 3A4, Pgp, MATE-1 2C9 Dolutegravir UGT, 3A4 MATE-1, OCT-2 Bictegravir UGT, 3A4 MATE-1, OCT-2

Antiretroviral Therapy Selection Choosing Between The Integrase Inhibitors Boosting Cobicistat and low-dose ritonavir are used to increase bioavailability and prolong t½ of elvitegravir and

28 Antiretroviral Therapy Selection Choosing Between The Integrase Inhibitors Boosting Cobicistat and low-dose ritonavir are used to increase bioavailability and prolong t½ of elvitegravir and protease inhibitors Activity primarily via Pgp inhibition and CYP 3A4 inhibition in the liver and GI tract Achieves higher and sustained troughs that limit the possibility of suboptimal levels

Antiretroviral Therapy Selection Choosing Between The Integrase Inhibitors Drug-Drug Interactions Elimination Cobicistat is an inhibitor of MATE-1 and therefore, inhibit active tubular secretion of

29 Antiretroviral Therapy Selection Choosing Between The Integrase Inhibitors Drug-Drug Interactions Elimination Cobicistat is an inhibitor of MATE-1 and therefore, inhibit active tubular secretion of creatinine SCr increases by ~10% within 1-2 weeks and plateaus Dolutegravir is an inhibitor of OCT2 and MATE-1 and can also inhibit active tubular secretion of creatinine SCr increases by ~10% within 1-2 weeks and plateaus Metformin is eliminated through OCT2 and MATE-1 AUC increase of 79% with dolutegravir AUC increase of 39% with bictegravir Dolutegravir Bictegravir Dolutegravir Bictegravir Cobicistat Dofetilideis eliminated through OCT2 and MATE-1 Contraindicated with dolutegravir and bictegravir

Tenofovir disoproxil fumarate (TDF) is a prodrug converted to tenofovir in the plasma and then enters the HIV target cell.

30 Antiretroviral Therapy Selection Tenofovir alafenamide (TAF) is a prodrug with 91% less circulating plasma tenofovir TAF reduces the risk of kidney injury and BMD losses in comparison to TDF Choosing Between NRTIs TDF or TAF? Tenofovir disoproxil fumarate (TDF) is a prodrug converted to tenofovir in the plasma and then enters the HIV target cell. TDF can lead to diminished renal function and losses in bone mineral density (BMD) Image adapted from Babusis D, et al. Mol Pharm. 2013;10(2):102:

31 Antiretroviral Therapy Selection Choosing Between NRTIs Abacavir Hypersensitivity Incidence = 5-8% Onset - within 6 weeks of initiating treatment Multi-organ system syndrome with symptoms from 2 of the following: Fever, rash, GI (nausea, vomiting, diarrhea or abdominal pain), malaise/fatigue, respiratory (cough or dyspnea) Can be fatal upon re-challenge HLA-B*5701 test has a 100% negative predictive value Mallal, et al. N Engl J Med 2008;358:568-79

32 Antiretroviral Therapy Selection Choosing Between NRTIs Abacavir and Cardiovascular Disease Risk Study Study Design Event (n) Patients (n) Abacavir Effect Risk of MI (95% CI) D:A:D Cohort MI (387) 22,625 Yes 1.70 ( ) D:A:D 2013 Cohort MI (493) 32,663 Yes 1.47 SMART RCT MI (19) 2,752 Yes 4.30 ( ) Danish Cohort MI (67) 2,952 Yes 2.00 ( ) VA Cohort CV event (501) 10,931 Yes 1.64 ( ) NA-ACCORD Cohort MI (301) 16,733 Yes 1.33 Swiss Cohort CVD event (350) 11,625 Yes 3.36 ( ) Swiss HIV Cohort Cohort CVD event (365) 11,856 Yes 2.06 ( )

33 Antiretroviral Therapy Selection Choosing Between NRTIs Abacavir and Cardiovascular Disease Risk Study Study Design Event (n) Patients (n) Abacavir Effect Risk of MI (95% CI) French Database CC MI (289) 74,958 No* 1.27 ( ) ALLRT/ACTG Cohort MI (36) 5,056 No 0.70 ( ) GSK Meta-analysis of RCTs MI (27) 14,174 No 0.17 ( ) VA Case Registry Cohort MI (278) 19,424 No 1.18 ( ) FDA Meta-analysis of RCTs MI (24) 9,868 No 1.02 ( ) *Without adjustment for cocaine use OR: 2.01 ( )

34 Antiretroviral Therapy Selection Choosing Between NRTIs Abacavir and Cardiovascular Disease Risk When selecting a regimen, a number of patient and regimen specific characteristic should be considered The goal is to provide a potent, safe, tolerable, and easy to adhere to regimen for the patient in order to achieve sustained virologic control CVD is one of several specific comorbidities listed among those to consider In patients with high cardiac risk, consider avoiding abacavir containing regimens Associated with increased cardiovascular risk in some but not all studies US DHHS. Guidelines for Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents Accessed March, 2018.

35 Summary Currently there are six targets for antiretroviral therapy agents within the HIV life cycle These agents differ in terms of efficacy, tolerability, safety, durability and their potential for drug-drug interactions All of these factors must be considered when selecting antiretroviral therapy for patients living with HIV

36 Antiretroviral Medications: What you need to know Jason J. Schafer, PharmD, MPH, BCPS, AAHIVP Associate Professor, Department of Pharmacy Practice Jefferson College of Pharmacy, Thomas Jefferson University

HIV Management Update 2015

9/30/15 HIV Management Update 2015 Larry Pineda, PharmD, PhC, BCPS Visiting Assistant Professor Pharmacy Practice and Administrative Science ljpineda@salud.unm.edu Pharmacist Learning Objectives Describe