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

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

http://www.txtwriter.com/Backgrounders/Aids/HIVLifecycle.gif

attack multiple targets to reduce

resistance & provide synergy
entry

attachment

Chemokine co-receptor
inhibitors
Fusion inhibitors

penetration
uncoating

Nucleoside Reverse Transcriptase inhibitors

Non-Nuc. Reverse Transcriptase inhibitors
Integrase inhibitors

nucleic acid synthesis

protein synthesis
packaging/assembly

Protease inhibitors

Maturation release

Adapted from Katzung et. al., Basic and Clinical Pharmacology

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

entry

attachment

penetration
uncoating
nucleic acid synthesis
protein synthesis
packaging/assembly

Maturation release

Adapted from Katzung et. al., Basic and Clinical Pharmacology

Fusion and Entry Inhibitors

ENFUVIRTIDE

MARAVIROC

Mechanism
of Action

binds to viral envelope

protein (GP 41) to
prevent viral entry

binds to chemokine coreceptor 5 (CCR5) to

prevent entry

Class side
effects

Injection site reactions

Rash, abdominal pain

Resistance

Mutations in HIV
envelope protein
decrease efficacy

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?

entry

attachment

penetration
uncoating
nucleic acid synthesis
protein synthesis
packaging/assembly

Maturation release

Adapted from Katzung et. al., Basic and Clinical Pharmacology

Nucleoside Reverse
Transcriptase Inhibitors
Also called

nucs, nuc backbone

Mechanism of
Action

Competitive inhibitors of viral dNA synthesis

Class side
effects

Mitochondrial toxicity, lactic acidosis, hepatic

steatosis, lipoatrophy

Resistance

Mutations in reverse transcriptase decrease

efficacy. Some target specific drugs, others cause
cross resistance.

NRTIs
Stavudine
base

Didanosine
Zidovudine

sugar

Emtricitabine
Lamivudine
Abacavir
deoxythymidine

Tenofovir

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)
B)
C)
D)

Zidovudine
Lamivudine
Atazanavir
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
Also called
Mechanism of
Action
Class side
effects
Resistance

non nucs

Large, bulkier, molecules. Allosteric inhibitors of

reverse transcriptase prevent viral DNA synthesis

Rash, hepatotoxicity

Single mutations (K103N) can impair. Cross

resistance present. Newer second generation
NNRTIs more robust versus resistance.

NRTI and NNRTI mechanisms

NNRTIs
Efavirenz
Nevirapine
Delavirdine
Etravirine
Rilpivirine

1:21 2:15

Content from: www.efp-online.org

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

entry

attachment

penetration
uncoating
nucleic acid synthesis
(integration)
protein synthesis
packaging/assembly

Maturation release

Adapted from Katzung et. al., Basic and Clinical Pharmacology

Integrase inhibitors
Also called

INIs, Instis (integrase strand transfer inhibitors)

Mechanism of
Action

Block the transfer of HIV DNA strand into the host

DNA

Class side
effects
Resistance

Single mutations can impair activity. Cross

resistance present. Newer second generation
more robust versus 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

entry

attachment

penetration
uncoating
nucleic acid synthesis
(integration)
protein synthesis
packaging/assembly

Maturation release

Adapted from Katzung et. al., Basic and Clinical Pharmacology

Protease Inhibitors
Also called
Mechanism of
Action

PIs

Competitive inhibitors bind to active site of

protease to prevent protein cleavage

Class Side
effects

GI upset. Metabolic effects: insulin resistance,

fat distribution, hypercholesterolemia

Resistance

Cross resistance amongst class members

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
Decreased variability in
trough concentrations

Incr AUC

Ritonavir inhibits CYP3A4- this interaction is used to our advantage!

Cobicistat also inhibits CYP3A4 no HIV activity

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

2015 Guideline Recommended Initial Treatment for HIV

General
Structure
2 NRTIs
PLUS
EITHER
1 PI +
ritonavir
OR
1
Integrase
inhibitor

Regimen
tenofovir/emtricitabine + darunavir + ritonavir
tenofovir/emtricitabine + dolutegravir
Abacavir/lamivudine/dolutegravir
tenofovir/emtricitabine/cobicistat/elvitegavir
tenofovir/emtricitabine + raltegravir

What type?

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