HIV Pharmacology PDF

W4D3 WIS Human Immunodeficiency Virus Pharmacology of Anti-Retroviral Therapy Akshith Dass, PharmD, BCIDP, BCPS Assistant Professor of Pharmacy Practice NEOMED December 6th, 2024 Slide Credits: Bhavin Mistry, PharmD, BCIDP,...

W4D3 WIS Human Immunodeficiency Virus Pharmacology of Anti-Retroviral Therapy Akshith Dass, PharmD, BCIDP, BCPS Assistant Professor of Pharmacy Practice NEOMED December 6th, 2024 Slide Credits: Bhavin Mistry, PharmD, BCIDP, BCPS Learning Objectives Describe the life cycle of HIV Describe the mechanism of action of anti-retroviral agents Distinguish the brand and generic names of anti-retroviral agents Appraise unique positive and negative attributes of anti-retroviral agents HIV Anti-Retroviral Therapy Resources Appendix B: Drug Characteristics Tables - (1-12) | NIH Core Concepts - Antiretroviral Medications and Initial Therapy - Antiretroviral Therapy - National HIV Curriculum Question Bank - National HIV Curriculum Banoub MF, Bailey JL, Bernice F. Human Immunodeficiency Virus Infection. In: Chisholm-Burns MA, Schwinghammer TL, Malone PM, Kolesar JM, Bookstaver P, Lee KC. eds. Pharmacotherapy Principles & Practice, 6e. McGraw-Hill Education; 2022. Accessed November 20, 2024. https://ppp.mhmedical.com/content.aspx?bookid=3114&sectionid=261467197 Flexner CW. Antiretroviral Agents and Treatment of HIV Infection. In: Brunton LL, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 14th Edition. McGraw-Hill Education; 2023. Accessed November 20, 2024. https://accesspharmacy.mhmedical.com/content.aspx?bookid=3191&sectionid=267906247 HIV Life Cycle reverse transcriptase RNA DIVA HIV Life Cycle Produced by the National Institute of Allergy and Infectious Diseases (NIAID), this illustration depicts the gp41 Fusion human immunodeficiency virus (HIV) replication cycle, Capsid gp Involving a host cell within the human body, (1) Beginning with a HIV virion attaching to the host CD4 cell cell wall, (T-lymphocyte) (2) Dumping its contents into the matrix of the host cell, Protease (3) Conversion of the viral RNA to viral DNA, which (4) Combines with the host cell DNA, (5) Leading to the creation of new viral RNA, which is used as messenger RNA to make viral proteins, which along with genomic RNA then (6) Migrates to the host cell periphery, and forms a Protease vacuole around the new viral RNA using the host cell (5) New viral RNA is used as wall, thereafter, messenger RNA and to make viral proteins (7) Budding off as a newly created mature HIV virion. protease breaks down proteins Produced by the National Institute of Allergy and Infectious Diseases (NIAID), this digitally colorized transmission electron microscopic (TEM) image, depicts a single human immunodeficiency virus (HIV), as it was budding from a human immune cell, which the virus had infected, and within which the HIV virus had been replicated. Details - Public Health Image Library(PHIL) Produced by the National Institute of Allergy and Infectious Diseases (NIAID), this digitally colorized scanning electron microscopic (SEM) image, depicts a single, red-colored, H9-T cell that had been infected by numerous, spheroid shaped, mustard- colored human immunodeficiency virus (HIV) particles, which can be seen attached to the cell's surface membrane. Details - Public Health Image Library(PHIL)  HIV Life Cycle with Anti-Retroviral Therapy CD4cell Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all Drug Classes Entry-Inhibitors Nucleoside/tide Reverse Transcription Inhibitors (NRTIs) Non-Nucleoside Reverse Transcription Inhibitors (NNRTIs) Integrase Inhibitors (INSTIs) Protease Inhibitors (PIs) Capsid inhibitor HIV Entry Inhibitors  HIV Entry 20 glycoprotein 120 chains gp 1. Attachment of HIV gp120 with host CD4 receptor 2. HIV gp120 binding with host chemokine coreceptor 3. HIV gp41 mediated fusion with host surface membrane Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all  atafmenG.PE iiiorFu5Feinsa ir Rukobia HIV Entry – Inhibitors Tom Ilbali2Umab Trogarz0 ihtiitt.hr CCRansfg.ee orMaraviroc Selzentry CD4/gp120 attachment inhibitor Binds to HIV iii niiniiio.ir Enfuviritide Fuzeon Fostemsavir Rukobia tab CD4 post-attachment inhibitor Binds to human cell surface receptor Ibalizumab IV Trogarzo CCR5 coreceptor antagonist Binds to human cell surface receptor Maraviroc tab sol Selzentry Fusion inhibitor Binds to HIV Enfuviritide Fuzeon SQ Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all  CD4/gp120 Attachment Inhibitor – Fostemsavir Fostemsavir (Rukobia) tablets Mechanism of Action gp41 Prodrug converted to temsavir gp120 (active form), which binds to the HIV gp120 subunit of HIV envelope proteins, inhibiting the interaction between the virus and the CD4 host Illustration: Cognition Studio, Inc. and David H. Spach, MD cell in stage 1 of the HIV life cycle (binding/attachment) Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all  CD4/gp120 Attachment Inhibitor – Fostemsavir Factoids ADME CYP3A4 substrate; avoid use with inducers Side effects Nausea Hepatotoxicity Renal failure Monitoring ALT, AST sCr Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  CD4-Post Attachment Inhibitor Anti-CD4 Monoclonal Antibody: Ibalizumab Ibalizumab (Trogarzo) IV Mechanism of Action Recombinant humanized monoclonal antibody which binds to Domain 2 of the CD4 receptor and through steric gp20 hinderance prevents the structural changes required in gp120 to bind to the chemokine coreceptor… prevents viral entry Acts at a step AFTER the gp120 binds Illustration: Cognition Studio, Inc. and David H. Spach, MD the CD4… Post-Attachment inhibitor Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  CD4-Post Attachment Inhibitor Anti-CD4 Monoclonal Antibody: Ibalizumab Factoids ADME Intravenous loading dose then maintenance dose every 14 days Side effects Diarrhea Dizziness Nausea Rash Renal failure Infusion related reaction Monitoring Observe for 1 hour after loading dose; 15 mins post-maintenance doses SCr Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  CCR5 Receptor Antagonist: Maraviroc Maraviroc (Selzentry) tablet and solution Mechanism of Action Binds to the CCR5 coreceptor causing a confirmational change in the coreceptor that prevents HIV gp120 from binding to the CCR5 coreceptor Illustration: Cognition Studio, Inc. and David H. Spach, MD Patients must be tested for Tropism BEFORE starting maraviroc maraviroc only works CCR5 vs CXCR4 vs CCR5 & CXCR4 on CCRS LOT CXCR4 Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Maraviroc Factoids ADME CYP3A4 substrate - Highly affected by inducers and inhibitors Side effects Skin rash Vomiting Upper respiratory tract infection Hepatotoxicity Orthostatic hypotension Monitoring LFTs Renal function Tropism test (prior to initiation) Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Fusion Inhibitor: Enfuvirtide Enfuvirtide (Fuzeon) subQ injection Mechanism of Action Binds to HIV gp41 preventing the normal interaction (fusion) between the HIV and CD4 host cell membranes Illustration: Cognition Studio, Inc. and David H. Spach, MD Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Fusion Inhibitor: Enfuvirtide Factoids ADME Subcutaneous injection only: Needle or BioJect (needle-free) maybe pulledoff Side effects Injection site reaction Increase rate of bacterial pneumonia market in 2025 Diarrhea, nausea Monitoring Injection site pain, erythema, induration, nodules and cysts, pruritus, ecchymosis CBC, LFTs Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  HIV Life Cycle with Anti-Retroviral Therapy Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all  Reverse Transcriptase Inhibitors  HIV Reverse Transcriptase HIV reverse transcription process HIV viral RNA dependent DNA polymerase Stranded HIV RNA  singlesSingle stranded HIV DNA Digestion of the HIV RNA Single stranded HIV DNA  Double stranded HIV DNA HIV reverse transcriptase incorporates human nucleotides into elongating primer Illustration: David H. Spach, MD strand which is opposite to the HIV template strand Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all HIV Reverse Transcription Inhibition Nucleoside reverse transcriptase inhibitors (NRTIs) Non-nucleoside reverse transcriptase inhibitors (NNRTIs)  Nucleoside Reverse Transcriptase Inhibitors Mechanism of Action sameaphemandes NRTIs are tri-phosphorylated intracellularly to an active state 043 P Triphosphorylated NRTIs mimic (and compete with) human nucleotides but without a 3’-hydroxylgroup and new nucleotides cannot be added to the NRTI drug NRTIs are taken up by HIV reverse transcriptase leading to chain termination when incorporated into the HIV DNA Illustration: David H. Spach, MD Prevents HIV RNA to be converted to HIV DNA Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all  Nucleoside Reverse Transcriptase Inhibitors Family Zidovudine (Retrovir) … Thymidine analog donimonthe Abacavir (Ziagen) … Thymidine analog analogs Lamivudine (Epivir) … Cytidine analog Emtricitabine (Emtriva) … Cytidine analog Tenofovir disoproxil fumarate (Viread)TDF … Adenine analog Nucleotide reverse transcriptase inhibitor Tenofovir alafenamide (Vemlidy) TAF … Adenine analog Nucleotide reverse transcriptase inhibitor Nucleotide pre phosphorylated DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. nuclegeHOT  TDF and TAF: Prodrugs of tenofovir (TFV) TDF: Hydrolyzed to TFV in plasma and then phosphorylated intracellularly (HIV cell)… High bone and renal side effects TAF: hydrolyzed and phosphorylated intracellularly (HIV cell)… relatively lower bone and renal side effects Wohl et al. Safety and Efficacy of TAF vs TDF Single-Tablet Regimen in HIV-1 Treatment-Naïve Black and Nonblack Patients Through Week 48. IDSA/IDWeek Oct 2015. Available here: https://www.natap.org/2015/IDSA/IDSA_19.htm  Nucleoside Reverse Transcriptase Inhibitor Combinations Emtricitabine / Tenofovir disoproxil fumarate (Truvada) Emtricitabine / Tenofovir alafenamide (Descovy) PrEP Lamivudine / Tenofovir disoproxil fumarate (CimDuo) Lamivudine / Abacavir (Epzicom) DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022.  Generalizing the NRTIs ADME All are given PO… Except for zidovudine – given IV to mother with HIV at the time of delivery Most are hepatically metabolized… Check drug interactions Side effects Lactic acidosis Hepatomegaly with steatosis Monitoring LFTs Renal function DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Agent Specific Toxicity Abacavir Test for HLA-B*5701 gene BEFORE initiating… Do NOT use if POSITIVE Hypersensitivity: Fever, rash, N/V, diarrhea, abdominal pain, malaise, fatigue, or respiratory symptoms Increased risk of myocardial infarction TDF TAF Tenofovir disoproxil fumarate more than Tenofovir alafenamide Renal toxicity (SCr ~10), proteinuria Bone demineralization (osteomalacia, osteoporosis) Tenofovir alafenamide more than Tenofovir disoproxil fumarate Weight gain Increased triglycerides, increased LDL, and decreased HDL DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Nucleoside Reverse Transcriptase Inhibitor – Resistance Secondary to mutations to the HIV’s reverse transcriptase Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Non-Nucleoside Reverse Transcriptase Inhibitors NNRTI Mechanism of Action NNRTIs bind non-competitively to a pocket which is close to the active site on the reverse transcriptase enzyme Causes a conformational change to the active site and the reverse transcriptase enzyme… blocks the process of DNA polymerization Illustration: Cognition Studio, Inc. and David H. Spach, MD Prevents HIV RNA to be converted to HIV DNA Same result as NRTI NNRTI binds to enzyme NRTI mimics nucleotides Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all  Non-Nucleoside Reverse Transcriptase Inhibitors Family Efavirenz (Sustiva) Etravirine (Intelence) Rilpivirine (Edurant) Doravirine (Pifeltro) DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  NNRTI Combination Atripla NRTI backbone Efavirenz + Emtricitabine + Tenofovir disoproxil fumarate Complera Rilpivirine + Emtricitabine + Tenofovir disoproxil fumarate Odefsey Rilpivirine + Emtricitabine + Tenofovir alafenamide Delstrigo Dorvarine + Emtricitabine + Tenofovir disoproxil fumarate DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Generalizing the NNRTIs ADME All PO INSTI In addition, rilpivirine available as IM formulation as part of a combination medication Highly protein bound Distributes to breast-milk Side effects Hepatotoxicity Rash Monitoring LFTs Major CYP3A4 substrates DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Agent Specific Toxicity Efavirenz CNS!... Neuropsychiatric symptoms (dizziness, vivid or abnormal dreams, confusion, insomnia, impaired concentration, agitation, hallucinations) About 50% may experience any of these symptoms but fewer than 5% discontinue the drug… resolve after 2-4 weeks Take on empty stomach, preferable at or before bedtime Teratogenic Etravirine Rash, nausea DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Agent Specific Toxicity Rilpivirine Depression Requires acidic environment Administer with a meal Administration with a protein supplement drink or yogurt alone is not adequate Avoid acid suppressants Do not use if HIV viral load > 100,000 copies/mL and/or CD4 count < 200 cells/mm3 High failure rate Doravirine… best side effect profile amongst NNRTIs Nausea Dizziness Abnormal dreams DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  NNRTI – Resistance Single amino acid changes in the NNRTI binding pocket mutation DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  HIV Life Cycle with Anti-Retroviral Therapy Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all Integrase Strand Transfer Inhibitors  HIV Integrase Enzyme HIV must incorporate double stranded HIV DNA into host DNA HIV integrase enzyme binds to each end of the newly formed HIV DNA and then integrates the HIV DNA strand into the host’s DNA integrase integrase integrase Illustration: Cognition Studio, Inc. and David H. Spach, MD Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all  Integrase Strand Transferase Inhibitors (INSTIs) INSTIs block the integrase strand transfer step by binding to the active site of the HIV integrase enzyme Binding of the INSTI to the integrase enzyme prevents the HIV DNA from integrating into the host DNA HIV DNA is degraded by the host’s repair enzymes Illustration: Cognition Studio, Inc. and David H. Spach, MD Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all  Integrase Strand Transfer Inhibitor (INSTIs) Family Raltegravir (Isentress) Elvitegravir Dolutegravir (Tivicay) Bictegravir Cabotegravir Vocabria; oral tablet Apretude; IM injection DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  INSTI Combinations Elvitegravir Stribild (elvitegravir-cobicistat-emtricitabine-tenofovir disoproxil fumarate) Genvoya (elvitegravir-cobicistat-emtricitabine-tenofovir alafenamide) Dolutegravir Juluca (dolutegravir-rilpivirine) Dovato (dolutegravir-lamivudine) Triumeq (dolutegravir-abacavir-lamivudine) HLAB 1907 Bictegravir Biktarvy (bictegravir-emtricitabine-tenofovir alafenamide) Cabotegravir Cabenuva (cabotegravir-rilpivirine) intramuscular DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Generalizing the INSTIs ADME Absorption affected by food Drug-Drug Interaction: Chelates with heavy cations CYP3A substrates – check drug interactions cobicistat elvitegravir Side effects Nausea, vomiting, headache Insomnia and mood changes Hyperlipidemia and Hyperbilirubinemia Monitoring CPK Renal function, cannot use when CrCl < 30 mL/min (not well studied) Liver function tests, lipid profile DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Agent Specific Toxicity Raltegravir Myopathy (muscle weakness); rhabdomyolysis Elvitegravir Combination with cobicistat (CYP-450 inhibitor [booster]) Stribild: CrCl < 70, use with caution; CrCl < 50, do not use Dolutegravir Weight gain Hypersensitivity reaction with severe rash and organ dysfunction (liver injury) Bictegravir Weight gain DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64. INSTI – resistance Very rare for HIV to have or develop INSTI resistance INSTIs can be used in setting of or even without knowledge of resistance to other agents  HIV Life Cycle with Anti-Retroviral Therapy Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all  Protease Inhibitors  HIV Protease Enzyme HIV Protease configuration Illustration: Cognition Studio, Inc. and David H. Spach, MD HIV + Human DNA is transcript-ed to HIV + Human RNA HIV + Human RNA is then transcript-ed to polyproteins Led HIV protease (molecular scissors) processes (snips) polyproteins to smaller components late in the HIV replication cycle… during and shortly after the virus is released from the host cell The processing (snipping) releases proteins for: Matrix, capsid, nucleocapsid, p6 protease, reverse transcriptase, integrase Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all Illustration: Cognition Studio, Inc. and David H. Spach, MD HIV Protease Inhibitors PIs bind to the active site of HIV protease enzyme and inhibit protease enzyme activity Halts the normal HIV maturation process… prevents infection of new cells PIs do not impact cells already infected with HIV (the HIV DNA is already incorporated into the host DNA) Illustration: Cognition Studio, Inc. and David H. Spach, MD  Protease Inhibitor Family Atazanavir (Reyataz) Darunavir (Prezista) DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Boosters or Pharmacokinetic Enhancers Ritonavir (Norvir) Developed as a PI but now used at a lower dose as a booster for other PI A/E: Hypertriglyceridemia, N/V/D Oral antiviral for COVID-19 Cobicistat (Tybost) No activity against HIV Inhibits creatine transport  Increased SCr but does not impact eGFR Boosters inhibit CYP enzymes, particularly CYP3A4 Decreased metabolism of CYP3A4 substrates Increased (boosted) concentration of the substrate to preventbreakdown ofdrug DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Protease Inhibitor Combinations Atazanir/cobicistat (Evotaz) Darunavir/cobicistat (Prezcobix) NRTI Darunavir/cobicistat-emtricitabine-tenofovir alafenamide (Symtuza) Lopinavir/ritonavir (Kaletra) DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Generalizing the PI’s ADME All are hepatically metabolized Pronounced inhibition of CYP3A4 – check drug-drug interactions Side effects Common gastro-intestinal (N/V/D) Hyperlipidemia side effects Hepatotoxicity Fat redistribution metabolic Monitoring LFTs Lipids DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Agent Specific Toxicity Atazanavir Acid labile Requires acidic environment for absorption; Administer with food Space out from PPI and H2RA Higher concentrations of serum bilirubin due to indirect bilirubin  Jaundice Not indicative of liver injury Nephrolithiasis (kidney stone due to crystal formation) Darunavir Contains a sulfa moiety – Similar incidence of rash in recipients with or without sulfonamide allergy Hepatotoxicity Diarrhea, nausea DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  Protease Inhibitor Resistance Mutations in the protease enzyme active site and secondary mutations distant from the active site Overall favorable resistance profile… used as 2nd line options for patients who have failed other anti-retroviral therapies NSTI 1Stline no resistance DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 12ed. McGraw-Hill Education. c2021. Chapter 148, Human Immunodeficiency Virus Infection. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Accessed November 2022. Flexner CW. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14ed. c2023. Chapter 64.  HIV Life Cycle with Anti-Retroviral Therapy Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all HIV Capsid Inhibitor  HIV Capsid Composed of HIV gp24 Encases Viral genome HIVRNA Reverse Transcriptase Integrase Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all  HIV Capsid Inhibitor: Lenacapavir Lenacapavir (Sunlenca) tablet and subQ Mechanism of Action Binds to HIV gp-24 subunit of the viral capsid, resulting in... Disruption of the transport of the capsid core through the nuclear pore complex Prevention of uncoating or disassembly of the capsid prevent Reassembly of the capsid core as part of HIV maturation process Illustration: Cognition Studio, Inc. and David H. Spach, MD Blocks the structure and function of the HIV capsid Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all  HIV Capsid Inhibitor: Lenacapavir Factoids Two induction regimens SQ loading dose, followed by oral regimen for 2 days Initial oral regimen on Day 1, 2, and 8, followed by a single SQ dose on day 15 Maintenance regimen every 6 months (SQ administration) +/- 2 weeks Side effects Injection site reactions Increase serum creatinine Monitoring Injection site erythema, induration, nodule, pruritus, pain, swelling sCr Sunlenca (lenacapavir) [package insert]. Foster City, CA: Gilead Sciences, Inc; 2022.  HIV Life Cycle with Anti-Retroviral Therapy Spach DH & Wood BR. Antiretroviral Medications and Initial Therapy. National HIV Curriculum. Available here: https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all