Pharmacology of

Antiviral Agents

Keith W. Crawford, R.Ph., Ph.D.

Department of Pharmacology
Howard University College of Medicine
HIV Life Cycle
 Pharmacologic strategies that block
viral entry and fusion
„ Enfuvirtide (Fuzeon)
- a peptide that binds gp41 and blocks interaction with
chemokine receptors
- administered SC 90mg BID
- most commonly used in salvage therapy

„ Chemokine receptor antagonists (investigational)

„ CD4+ monoclonal antibody (investigational)

Nucleoside reverse transcriptase Inhibitors
(NRTI’s) require metabolic activation
„ DNA synthesis uses nucleoTIDES. Nucleotides
are triphosphates.

„ NucleoSIDES must be phosphorylated

sequentially by host enzymes to generate active
nucleotides analogues.

„ The drug tenofovir is a nucleoTIDE analog and

does not require activation.
Mechanism of action of Nucleoside
Reverse transcriptase Inhibitors (NRTI’s)

„ NRTI’s compete with the incorporation of

nucleotides in DNA synthesis

„ These drugs lack the hydroxyl group necessary to

form a phosphodiester linkage for DNA chain
growth. Hence, the incorporation of these drugs
into a growing DNA chain results in chain
termination.
 Common toxicities of NRTI’s may
involve the drug inhibition of γ-
polymerase and mitochondrial toxicity

„ Lactic acidosis
„ Peripheral neuropathy
„ Myopathy
„ Lipoatrophy
Approved NRTI drugs
„ Zidovudine (AZT) „ Lamivudine (3TC)

„ Didanosine (ddI) „ Emtricitabine (FTC)

„ Abacavir
„ Zalcitabine (ddC)

„ Tenofovir – This
„ Stavudine (d4T) drug is actually a
nucleoTIDE analog;
it does not require
activation
Combination NRTI products
„ Combivir (zidovudine/lamivudine)

„ Epsicom (abacavir/lamivudine)

„ Truvada (tenofovir/emtricitabine)

„ Trizivir (abacavir/zidovudine/lamivudine)
Non-Nucleoside Reverse Transcriptase
Inhibitors (NNRTI’s)
„ Inhibit Reverse Transcriptase non-competitively at a
site distinct from where NRTI’s act

„ Some of these agents are among the most potent

anti-retrovirals (e.g. efavirenz)

„ Good CNS penetration

„ Acquisition of a single high-level resistance mutation

confers cross resistance throughout the class
Major Toxicities of NNRTI’s

„ Rash – may be mild with efavirenz or nevirapine;

nevirapine can cause a serious rash that can be life-
threatening
„ Hepatotoxity – Nevirapine can cause life-threatening liver
disease particular in patients with relatively good immune
function (Do not use in men with CD4+> 400, women
>250).
„ CNS side-effects – efavirenz vcan cause dizziness,
disorientation, vivid dreams and other distubing effects.
Effect usually diminish with time, administering the drug
before going to bed minimizes the effects.
Approved NNRTI’s
„ Efavirenz

„ Nevirapine

„ Delavridine

„ Atripla (combination of efavirenz, tenofovir and

emtricibine; one pill once a day)
 Protease Inhibitors (PIs)
„ Among the most potent inhibitors of HIV replication (>1 log
decrease in HIV RNA)

„ Reach high concentrations in the lymphoid tissues

„ Poor penetration into the CNS (except indinavir and

atazanavir)

„ These agents are often combined, utilizing the competition for

metabolism to pharmacokinetically enhance plasma drug
levels. Low-doses of the PI ritonavir (sub-therapeutic)
pharmacokinetically enhance plasma levels of other PI’s (e.g.
the PI lopinavir is co-formulated with low-dose ritonavir in the
product KaletraR).
Effects of Anti-retrovirals on Drug
metabolism
„ Protease inhibitors are primarily metabolized by
CYP3A4, but other pathways are also important.
Ritonavir is the most potent CYP450 inhibitor in clinical
use. Atazanavir also inhibits CYP’s while
amprenavir/fosamprenavir are inducers.

„ NNRTI’s efavirenz and nevirapine are CYP450 inducers.

They can accelarate the metabolism of many drugs.
 Enzyme Inhibition and Induction
Drug Enzyme Inhibition Enzyme Induction

Atazanavir ++ —

Delavirdine ++ —

Efavirenz + +++

Fosamprenavir + ++

Indinavir ++ —

Lopinavir/ritonavir[1] ++++ ++

Tipranavir/ritonavir[1] ++++ +++

Nelfinavir ++ +

Nevirapine — ++

Ritonavir ++++ ++

Saquinavir[2] — —
Approved Protease Inhibitors
„ Saquinavir „ Fosamprenavir (a
„ Ritonavir prodrug of Amprenavir)
„ Indinavir „ Atazanavir
„ Nelfinavir „ Tipranavir
„ Amprenavir „ Darunavir
Some Metabolic Toxicities of
Protease Inhibitors
 HAART and the Risk of Myocardial
Infarction: Updated Data From D:A:D
► Exposure to elements of HAART
ƒ NNRTI: 6.3 years (3.8-8.3)
ƒ PI: 3.0 (0.5-5.4) RR of MI by ART Exposure
ƒ NNRTI: 0.9 (0-3.2)
1.8
► Peak RR of MI in 2001; falling 1.6
since
1.4
► Adjustment for lipids largely
explains decline in MI 1.2

RR of MI
► PI exposure associated with 1.0
similar increased risk as HAART 0.8 ART PI* NNRTI†
exposure 0.6
► NNRTI exposure not associated 0.4
with increased risk of MI
0.2
► Adjustment for NRTI exposure
did not change risk 0
*Adjusted for NNRTI exposure.
► Suggests that increased risk †Adjusted for PI exposure.

previously reported with HAART

largely driven by PIs
El-Sadr W, et al. CROI 2006. Abstract 144.
 Metabolic Effects of PIs

Lipids Glucose
RTV ↑ TC/TG ↑ insulin resistance
LPV ↑ TC/TG ↑ insulin resistance
IDV ↑ TC/TG ↑ insulin resistance
NFV ↑ LDL/TG, ↓ HDL no Δ insulin sensitivity
APV/FPV ↑ TC/TG no Δ insulin sensitivity
TPV ↑ TC/TG ?
SQV no Δ no Δ insulin sensitivity
ATV no Δ no Δ insulin sensitivity
Evaluating response to Highly Active
Anti-Retroviral Therapy (HAART)
 Rationale for combining
anti-retrovirals (HAART)

„ Greater reduction in plasma viral load/ increased

CD4+ lymphocytes

„ More durable suppression

„ Reduction in the time to develop resistance

„ Pharmacokinetic/dynamic synergy
 Guidelines for starting Antiretrovirals
„ AIDS-defining illness (e.g. PCP); symptomatic at any
CD4+ cell count, Treatment recommended

„ Assymptomatic, CD4+ cells < 200, Treatment

recommended

„ Asymptomatic, CD4+ cells = 201-350

Offer treatment

„ Asymptomatic, CD4+ cells > 350 but HIV RNA >100,000

copies, Offer treatment
„ CD4+ cell >350, HIV RNA < 100,000 copies, Defer
treatment
Nucleoside Analogue Anti-virals (Non-HIV)
„ Like to NRTI’s, these agents also require
metabolism to active triphosphates.

„ Phosphorylations are usually initiated by

viral kinases, followed by host cell kinases.
Viruses can mutate their enzymes to
decrease drug activation leading to drug
resistance

„ The activated drugs compete with

nucleotides in DNA synthesis and produce
chain termination when inserted
Acyclovir – an analogue of 2’-deoxguanosine
„ Active against HSV, VZV, prophylaxis of CMV

„ HSV-encoded thymidine kinase forms acyclovir

monophosphate, subsequent phosphorylations utilize host
enzyme

„ Acyclovir triphosphate is 30-50 fold more potent inhibiting

HSV DNA polymerase than human α-DNA polymerase

„ Valacyclovir- l-valyl ester of acyclovir, a prodrug

metabolized to yield acyclovir concentrations 3-5X higher
than acyclovir preparations
Gancyclovir/Valgancyclovir
„ Gancyclovir- activity against CMV, HSV I and II, EBV,
VSV, HH8

„ CMV-encoded phosphotransferase activates ganciclovir to

ganciclovir monophosphate

„ Valgancyclovir-the valine ester prodrug of gancyclovir

produces significantly higher blood levels of gancyclovir

„ Toxicities – Hematologic: Granulocytopenia,

thrombocytopenia, anemia, CNS disturbances
Cidofovir
„ Does not require viral enzymes to activate it.
Host enzymes metabolize the drug to cidofovir
diphosphate, the active form

„ Active against CMV, acyclovir-resistant HSV,

VSV, topical gel for HPV

„ Nephotoxicity: administer with probenecid;

neutropenia; increased intra-ocular pressure may
occur
Pyrrophosphate analogue - Foscarnet
„ Active against CMV, VZV, acyclovir-resistant HSV, EBV,
HBV
„ Foscarnet binds viral DNA polymerase at the
pyrophosphate binding site, preventing the cleavage of
pyrophosphate from nucleoside triphosphates, thus
blocking primer-template extensions
„ Toxicities
- decreased creatinine clearance and acute renal failure
occur in about 1/3 of patients

- Electrolyte abnormalities (hypocalcemia,

hypo/hyperphosphatemia, hypomagnesemia,
hypokalemia.

- Also, fever, GI disturbances, headaches occur rather

frequently
Ribavirin

„ Activity against RSV, HCV, Infuenza A&B, Hantavirus

„ A guanosine analogue activated in virally-infected cells

„ Believed to inhibit early steps in viral gene transcription

by interfering with capping and elongation of mRNA.
Ribavirin introduces mutations to viral mRNA leading to
non-functional proteins.

„ Toxicities - anemia
 Neuraminidase Inhibitors (Zanamavir,
Oseltamavir)

„ Activity against influenza A and B virus; active against

avian influenza

„ Neuraminidase is a surface glycoprotein of infuenza A and

B. It cleaves terminal sialic acid residues from
glycoconjugate which:
- Allows virion release from infected cells
- Prevents aggregation of virions
- Reduces inactivation of virus by respiratory tract mucus
Inhibitors of M2 protein
„ M2 is an integral membrane protein that functions
as an ion channel. Uncoating of the virus and
nuclear transport of viral genetic material require
and acidic environment maintained by M2

„ Amantadine and Rimantadine inhibit M2 function

in influenza A virus

„ These drugs have central dopaminergic activity

and Amandatine is used in treating Parkinson’s
Disease
Treatments for HBV

„ Lamivudine and Tenofovir have activity against HBV and

are also anti-retroviral agents. Because many patients are
HBV/HIV co-infected, and these drugs have low toxicity,
they are extremely useful agents

„ Adefovir

„ Entecavir – a recently approved nucleoside analogue with

potent activity against drug-resistant HBV

„ Alpha interferon
„ Clinical Care Options Hepatitis - Life
Cycle of Hepatitis C Virus
Interferons
„ Cytokines with potent broad-spectrum anti-viral activities
(HTLV-II, HH8, HPV, HBV, HCV, HIV)

„ Interferons induce the synthesis of a host of proteins that

can block viral transcription and translation

„ 2’-5’Oligo-adenylate synthase/RNaseL –degrades dsRNA,

inhibit viral protein synthesis

„ Interferon inducible kinase phosphorylates eIF-2 which

inhibits translation initiation, block viral protein synthesis
Pegylated Interferons
„ Coupling a polyethylene glycol (PEG) moiety to
interferon remarkably enhances the
pharmacokinetic chararcteristics and efficacy of
the drug.
„ Dosing frequency is reduced due to the extended
half-life.
„ Therapeutic effects are improved over regular
alpha-interferon
„ Pegylated interferons with high-dose ribavirin
produce the best responses to HCV
„ Pegasys, PegIntron