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