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Antivirals IV: HIV Pharmacology
Jennifer Cocohoba, PharmD, AAHIVP Health Sciences Associate Clinical Professor
UCSF School of Pharmacy & Clinical Pharmacist, UCSF Womens HIV Clinic
Goals & Objectives Review antiretroviral agents used in the treatment of HIV
Understand rationale for combination therapy Review different drug classes and their mechanism of action Review major drug class side effects
http://www.txtwriter.com/Backgrounders/Aids/HIVLifecycle.gif
Principle: HIV viral resistance develops rapidly
Reverse transcriptase makes errors 1/2000 1/10000 nucleotides
Envelope proteins (GP 120) variable
Challenging for
vaccine development and resistance
attack multiple targets to reduce resistance & provide synergy
Maturation release
entry attachment penetration
uncoating
nucleic acid synthesis
protein synthesis
packaging/assembly
Adapted from Katzung et. al., Basic and Clinical Pharmacology
Chemokine co-receptor inhibitors
Fusion inhibitors
Nucleoside Reverse Transcriptase inhibitors Non-Nuc. Reverse Transcriptase inhibitors Integrase inhibitors
Protease inhibitors
Organizing the HIV drugs Organized in classes, defined by mechanism of action
CCR5 (entry) inhibitors Fusion inhibitors Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Non-nucleoside Reverse Transcriptase Inhibitors Integrase inhibitors Protease inhibitors
Names can fool you no good patterns Protease inhibitors: lopinavir, darunavir NRTIs: abacavir, tenofovir Integrase inhibitors: raltegravir, dolutegravir
HIV therapeutics
Now New combination dosing forms Me-too agents = better vs. resistance & side effects
Viral suppression achievable for most patients New modes of thinking
Pre-exposure prophylaxis, test and treat
Maturation release
entry attachment penetration
uncoating
nucleic acid synthesis
protein synthesis
packaging/assembly
Adapted from Katzung et. al., Basic and Clinical Pharmacology
Fusion and Entry Inhibitors
binds to viral envelope protein (GP 41) to prevent viral entry
Mechanism of Action
Injection site reactions Class side effects
Mutations in HIV envelope protein decrease efficacy
Resistance
binds to chemokine co-receptor 5 (CCR5) to prevent entry
ENFUVIRTIDE MARAVIROC
Rash, abdominal pain
Resistance possible. Doesnt work if virus uses CXCR4 co-receptor for entry
Entry Inhibitors
Case
You are about to start antiretroviral therapy on a patient. Which drug does
this test assess? Will the drug work
in this patient?
Maturation release
entry attachment penetration
uncoating
nucleic acid synthesis
protein synthesis
packaging/assembly
Adapted from Katzung et. al., Basic and Clinical Pharmacology
Nucleoside Reverse Transcriptase Inhibitors
nucs, nuc backbone Also called
Competitive inhibitors of viral dNA synthesis Mechanism of Action
Mitochondrial toxicity, lactic acidosis, hepatic steatosis, lipoatrophy
Class side effects
Mutations in reverse transcriptase decrease efficacy. Some target specific drugs, others cause cross resistance.
Resistance
NRTIs Stavudine
Didanosine
Zidovudine
Emtricitabine
Lamivudine
Abacavir
Tenofovir deoxythymidine
base
sugar
NRTI Specific Side effects
Name (More Common/Important) Side Effects Why important Zidovudine Nausea, anemia, headache 1st HIV drug Lamivudine Well tolerated In many combos
Often 1st line
Emtricitabine Well tolerated In many combos Often 1st line
Abacavir Hypersensitivity reaction, nausea Often 1st line Allergy reaction
Tenofovir Renal toxicity, nausea, flatulence Often 1st line
Abacavir Hypersensitivity
One of few pharmacogenomic tests incorporated into practice as standard care = HLAB*5701 test for abacavir hypersensitivity
Check your understanding A 27 year old female patient
comes to clinic 2 weeks after starting new antiretroviral medicines. Pertinent labs are below. What is the most likely culprit?
CD4: 350 cells/mm3 Viral load: 2560 c/mL Hgb: 12 (normal 12-15) Hct: 38% (normal 38-46%) Serum Creatinine: 1.7 mg/dL (normal 0.6 1.1)
A) Zidovudine B) Lamivudine C) Atazanavir D) Tenofovir
Check your understanding
A 56 year old female is coming to your clinic hoping to switch to a more simple HIV regimen. She would like to be on the single tablet abacavir/lamivudine/dolutegravir. With the information you have thusfar, would this be a possible regimen for her?
Non-Nucleoside Reverse Transcriptase Inhibitors
non nucs Also called
Large, bulkier, molecules. Allosteric inhibitors of reverse transcriptase prevent viral DNA synthesis
Mechanism of Action
Rash, hepatotoxicity Class side effects
Single mutations (K103N) can impair. Cross resistance present. Newer second generation NNRTIs more robust versus resistance.
Resistance
NRTI and NNRTI mechanisms
NNRTIs Efavirenz Nevirapine Delavirdine Etravirine Rilpivirine
Content from: www.efp-online.org 1:21 2:15
Selected NNRTI Side Effects
Name (More Common/Important) Side effects Why important Efavirenz Rash, hepatotoxicity
Vivid dreams, dizziness, grogginess, Widely used, first line
Nevirapine Rash, hepatotoxicity (depends on CD4+ count and gender!), Hypersensitivity, nausea
Widely used internationally
Etravirine Rash, hepatotoxicity, nausea, lipids
2nd generation NNRTI
Rilpivirine Rash, hepatotoxicity, 2nd generation NNRTI
Check your understanding
Which of the following NNRTI antiretrovirals is associated with a serious hypersensitivity reaction which may involve hepatotoxicity, rash, and fever?
A) zidovudine B) etravirine C)nevirapine D) tenofovir
Case A patient started his
first antiretroviral regimen 2 days ago. He is irritable because he cant sleep due to crazy scary dreams, and wakes up feeling fuzzy in the morning. Which medicine is the likely culprit?
A) tenofovir B) etravirine C) nevirapine D) efavirenz
Maturation release
entry attachment penetration
uncoating
nucleic acid synthesis
protein synthesis
packaging/assembly
Adapted from Katzung et. al., Basic and Clinical Pharmacology
(integration)
Integrase inhibitors
INIs, Instis (integrase strand transfer inhibitors) Also called
Block the transfer of HIV DNA strand into the host DNA
Mechanism of Action
? Class side effects
Single mutations can impair activity. Cross resistance present. Newer second generation more robust versus resistance.
Resistance
Selected Integrase Inhibitor(s) Name (More Common/Important) Side Effects Why important
raltegravir Well tolerated! Possible nausea, lipids, hepatotoxicity
1st integrase inhibitor 1st line
dolutegravir Well tolerated! Headache, insomnia (?), liver inflammation
1st line
elvitegravir Well tolerated Elevation in creatinine (booster), drug-interactions
1st line
Maturation release
entry attachment penetration
uncoating
nucleic acid synthesis
protein synthesis
packaging/assembly
Adapted from Katzung et. al., Basic and Clinical Pharmacology
(integration)
Protease Inhibitors
PIs Also called
Competitive inhibitors bind to active site of protease to prevent protein cleavage
Mechanism of Action
GI upset. Metabolic effects: insulin resistance, fat distribution, hypercholesterolemia
Class Side effects
Cross resistance amongst class members Resistance
Protease inhibitors & mortality
Palella FJ, NEJM, 1998
Selected Protease Inhibitor Notes Name (More common/Important)
Side Effects Why important
Ritonavir Diarrhea, nausea, lipid, taste disturbances
Used for PK boosting
Lopinavir/ ritonavir
Diarrhea, nausea, lipid abnomalities, insulin resistance
1st co-formulated with ritonavir
Atazanavir Hyperbilirubinemia, rash 1st line Darunavir Nausea/vomiting, diarrhea 1st line
Other protease inhibitors: saquinavir, nelfinavir, indinavir, tipranavir, amprenavir, fosamprenavir
Principle: pharmacokinetic boosting
Ritonavir inhibits CYP3A4- this interaction is used to our advantage! Cobicistat also inhibits CYP3A4 no HIV activity
Decreased variability in trough concentrations
Incr AUC
Check your understanding
A patient is newly starting antiretroviral therapy. She wants a once-daily regime. Which of these agents should be added to her regimen to increase the plasma levels of her darunavir?
A) cobicistat B) ritonavir C) tenofovir D) lamivudine
Check your understanding
A pregnant woman is starting a regimen that includes lopinavir/ritonavir. Which lab value should be followed to assess for one of the medicines common side effects?
A) Complete blood count B) Serum creatinine C)Blood glucose D)Total Bilirubin
Check your understanding A young man
presents to clinic with scleral icterus and yellow-toned skin 6 weeks after starting antiretroviral therapy. He reports no fevers, rash, or abdominal pain. Which medication is causing this side effect?
A) Abacavir B) Atazanavir C)Lopinavir/ritonavir D)Efavirenz
Putting the regimen together
General Structure 2 NRTIs PLUS EITHER
1 PI + ritonavir
OR 1
Integrase inhibitor
2015 Guideline Recommended Initial Treatment for HIV
Regimen What type?
tenofovir/emtricitabine + darunavir + ritonavir tenofovir/emtricitabine + dolutegravir Abacavir/lamivudine/dolutegravir tenofovir/emtricitabine/cobicistat/elvitegavir tenofovir/emtricitabine + raltegravir
Links to videos
HIV life cycle overview https://www.youtube.com/watch?
v=RO8MP3wMvqg&index=3&list=PL40D9794BBFAA04A5
NRTI and NNRTI video http://www.youtube.com/watch?v=h7V1eVwxV_c Entry Inhibitors http://www.thebody.com/content/toparts/art48577.html