M.

10 ANTIVIRAL CHEMOTHERAPY AND PROPHYLAXIS

Dr. Dominguez | March 21, 2018

I. ANTIVIRAL AGENTS

AGENTS against HSV and VZV

DRUG MOA/MOR INDICATIONS PK (ROA, ADME, DRUG INTERACTIONS) TOXICITIES/ADRs
GENERAL MOA (Mechanism of Action) and MOR (Mode of Resistance): Excretion:
1. Inhibition of viral DNA synthesis Renal clearance
− Their main mechanism of action is they inhibit the viral DNA polymerase and they also inhibit − Risk of nephrotoxicity
the incorporation of the viral DNA into the cells and cause viral DNA chain termination
− Begins with triple phosphorylation of the drugs by viral thymidine kinase
! Acyclovir, Valacyclovir, and Famciclovir will need the viral kinase for activation so if the
cells are not infected with the virus, then these drugs will not have an effect on the cells.
These drugs would be selective only for virally-infected cells.
− Competitive inhibition of viral DNA polymerase → inhibition of viral DNA synthesis
− Makes drugs more concentrated on viral cells (and not human cells, because they do not have these
viral enzymes)
− MC MOR: Deficiency in the act of viral thymidine kinase
o Also causes cross resistance with Valacyclovir, Penciclovir, and Famciclovir
! If a person is resistant to Acyclovir, they will also be resistant to Valacyclovir and
Famciclovir by virtue of this phosphorylation reaction
2. Chain termination (only by Acyclovir: 2 MOAs)
3. Require viral kinase for phosphorylation for activation
ACYCLOVIR MOA: ROA: Oral, IV, Topical
• Inhibition of viral DNA synthesis − Orally: 5x a day
• Chain termination − Reversible renal toxicity with IV infusion
− Most common toxicity is renal toxicity
MOR: especially if it is given parenterally but
Deficiency in the activity of viral as long as you hydrate the patient and
thymidine kinase monitor the infusion rate then we can
prevent nephrotoxicity

Excretion:
− Reduced clearance with Probenecid and
Cimetidine
o Remedy: Reduce dose of acyclovir
if to be given with these drugs
− Causes somnolence and lethargy if used
concomitantly with Zidovudine
(antiretroviral drug vs. HIV)
VALACYCLOVIR Oral Valacyclovir levels = IV Acyclovir
L-valyl ester of Acyclovir (given 3x a day)
− Valacyclovir efficacy is similar to IV
Acyclovir that’s why we are shying away
from Acyclovir and going more into
Valacyclovir (more convenient, same
efficacy as that of the IV Acacylovir)

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FAMCICLOVIR Blocks DNA synthesis (it will only Active against Epstein-Barr Virus and ADRs: headache, nausea, and
Prodrug of Penciclovir (active cause inhibition of viral DNA Hepatitis B Virus vomiting
metabolite) polymerase) but DOES NOT affect
chain termination
OTHER AGENTS against HSV and VZV
DOCOSANOL Inhibits fusion between plasma Topical
membrane and HSV (1st step in viral
life cycle)
TRIFLURIDINE 1. Inhibit viral DNA synthesis 1. Main indication: Very toxic since it also binds to host cells i.e.
2. Does not require viral kinases Keratoconjunctivitis associated requires host kinases for phosphorylation
for activation), bypassing the with HSV
thymidine kinase step
(alternative when patients are 2. Given to patients with resistance to
resistant to the first three drugs) Acyclovir, Valacyclovir, and
3. But require host kinases Famciclovir

AGENTS against CMV

DRUG MOA/MOR INDICATIONS PK (ROA, ADME, DRUG INTERACTIONS) TOXICITIES/ADRs
Cytomegalovirus infections are very common among post-transplant patients
MOA: Generally inhibit nucleic acid synthesis
GANCICLOVIR 1. Inhibition of viral DNA synthesis ROA: Most common ADR:
VALGANCICLOVIR 2. Also causes chain termination (like Acyclovir) Oral, IV, intraocular implants Myelosuppression
3. Also requires triple phosphorylation (also requires
viral kinase for phosphorylation/for activation)
FOSCARNET 1. Directly inhibits viral DNA and RNA polymerase, and Alternative to ROA:
HIV reverse transcriptase (all others: competitive Acyclovir IV preparations only due to
inhibitors) a. Poor bioavailability
2. Does not require phosphorylation b. GI intolerance
CIDOFOVIR 1. Inhibits viral DNA synthesis 1. Nephrotoxicity
2. Does not require viral thymidine kinase Remedy: Administer with
Probenecid to decrease toxicity
2. Causes ocular toxicity

ANTIRETROVIRAL DRUGS
*Minimum of at least 3 antiretrovirals from different classes to prevent resistance
DRUG CLASS MOA/MOR DRUG INDICATIONS TOXICITIES/ADRs
Nucleoside/Nucleotide reverse MOA: ABACAVIR Recommended for use in pregnant Mitochondrial toxicity manifesting
transcriptase inhibitors (NRTIs) 1. NRTIs cause competitive inhibition women as:
of HIV-1 reverse transcriptase 1. Lactic acidosis (ABGs: metabolic
Nucleoside/Nucleotide: enzyme acidosis) with hepatic steatosis
analogues of the virus 2. Require phosphorylation for (rapidly elevating SGOT, SGPT
activation levels)
*Reverse transcriptase: Converts Remedy: immediately discontinue
viral RNA into DNA → viral DNA is the NRTIs
incorporated into human DNA

2. Most common cause of death in

HIC is cardiovascular side effects
from NRTIs

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" Fatal hypersensitivity

HLA Ag Testing to r/o HSx = if (-)
then safe to give
" MI
− In recent studies, patients do
not die of opportunistic
infections. They die of cardiac
complications brought about
by the drug.
" Increased levels with alcohol
ingestion
DIDANOSINE " Pancreatitis
− Increases triglyceride levels
− Caution in alcoholics
" MI
EMTRICITABINE Recommended for use in pregnant " Hepatitis flares
Previously a 2nd line drug women − Hepatitis B infections are
common in HIV
− Sudden termination of drug:
reactivation of Hepatitis B
" Caution with oral preparation
because it contains propylene glycol
which is contraindicated in pregnant
women, children, and those taking
Metronidazole
" Also causes renal and hepatic
failure
LAMIVUDINE Recommended for use in pregnant " Hepatitis flares
Previously a 2nd line drug women
For Patients With Hepatitis B (Chronic
Hepatitis B)
− It is common for HIV
patients to have concomitant
Hepatitis B
STAVUDINE " Peripheral sensory neuropathy
TENOFOVIR Recommended for use in pregnant " Diarrhea
women " Flatulence
− Not recommended for lactose
intolerant patients
" Osteoporosis: decreases bone
density
ZALCITABINE " Peripheral neuropathy
" Oral and esophageal ulcerations
ZIDOVUDINE/AZT/ Recommended for use in pregnant " Myelosuppression
AZIDOTHYMIDINE women
First approved antiretroviral


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Non-nucleoside reverse 1. Direct binding to HIV-1 reverse DELAVIRDINE EFAVIRENZ and RILPIVIRINE Toxicities:
transcriptase inhibitors (NNRTIs) transcriptase causing ETRAVIRINE − Recommended for use in 1. GI intolerance
conformational change in the EFAVIRENZ pregnant women 2. Rashes which can progress to SJS
Non-nucleoside analogues but inhibit enzyme (has a different binding RILPIVIRINE
the same enzyme as NRTIs, which is site on the enzyme as opposed to NEVIRAPINE NEVIRAPINE EFAVIRENZ
reverse transcriptase the NRTIs) − Previously recommended for − CNS symptoms
Metabolized by CYP450 that’s why you use in pregnant women with
2. Do not require phosphorylation would expect a lot of drug-to-drug HIV but now, it is no longer
in contrast to NRTIs interactions, either with the other recommended
antiretroviral agents or other drugs
Protease inhibitors (PI) 1. General MOA: When combined with Ritonavir Toxicities:
(-navir) − Prevents formation (inhibits − Pharmacologic booster 1. Cushingoid appearance except
the release) of mature − Ritonavir will enhance the effect Atazanamir
virions (last step in viral life of the different protease 2. Increased TG, LDL, glucose,
cycle) inhibitors insulin resistance
− Prevent processing of viral − Increases serum levels of other
proteins producing protease inhibitors Prone to PR and QT prolongation
immature, non-infectious − Patients on protease
virions Metabolized extensively by CYP3A4 → inhibitors should have a
2. Does not require intracellular possibility of drug interactions baseline ECG
activation or phosphorylation − Contraindicated if patient has
a prolonged QT → they
would cause fatal
arrhythmias
ATAZANAVIR Recommended for use in pregnant " GI effects
women " No metabolic toxicities or fat
redistribution
" Only PI not to bring about
Cushingoid appearance
" Reduced levels with PPIs
− Give 12 hours apart
DARUNAVIR Recommended for use in pregnancy
FOSAMPRENAVIR " Allergic reactions if patient is
− Oral solution with propylene allergic to sulfa drugs
glycol (same caution as
Emtricitabine) and Vitamin E
− Sulfonamide-derived
INDINAVIR " Hyperbilirubinemia
" Nephrolithiasis
LOPINAVIR Recommended for use in pregnancy
NELFINAVIR Alternative in pregnancy
RITONAVIR Recommended for use in pregnant
Pharmacologic boosting: enhance women
effect of PIs
SAQUINAVIR Alternative in pregnancy Do not use Saquinavir and Ritonavir
together: enhances QT prolongation
→ develop Torsades de Pointes
TIPRANAVIR indicated for use in tx-experienced Contraindicated in patients with hepatic
(Newer PI) HIV-1-infected Pt who harbor strains insufficiency
resistant to other PI agents

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Fusion/Entry inhibitor
CCR5 co-receptor antagonist
Integrase strand transfer
inhibitors (INSTIs)
(-gravir)
Blocks entry (first step) of virus into ENFUVIRTIDE Not yet licensed for use in pregnancy Most common adverse effect:
cell by preventing binding or fusion of ROA: Parenteral Injection site reactions
viral envelope glycoproteins to the
CD4+ receptors thus preventing entry Previously included Maraviroc
of HIV into the host cells
Separated from fusion inhibitors MARAVIROC May trigger MI
because it has a different point of
action Metabolized by CYP 3A4 → prone to A good practice would be if the patient
− Binds specifically and selectively more drug-drug interactions has a lot of risk factors for MI, use
to CCR5, one of two co-receptors other drugs
necessary for entrance of HIV
into CD4+ cells, thus blocking
entry of CCR5-tropic HIV into
these cells
1. Interfere with integration of RALTEGRAVIR RALTEGRAVIR " Insomnia, headache, diarrhea,
reverse-transcribed HIV DNA into ELVITEGRAVIR − Recommended for use in nausea, dizziness, and fatigue
host cell chromosome DOLUTEGRAVIR pregnant women " Increase in creatine kinase may
2. Prevent integration of viral DNA occur, with potential myopathy or
into host cell DNA rhabdomyolysis

PrimaryGoals:
1. Not to eradicate virus but induce SEROCONVERSION [From Hbe Ag(+) to Hbe Ag(-)]
2. Lower HBV DNA to undetectable levels
3. Reduce transaminase levels
DRUG CLASS
INTERFERON ALFA
PEGYLATED INTERFERON
− A modification of interferon alfa
to reduce the toxicity
− With polyethylene glycol (PEG)
as carrier
MOA/MOR
1. Inhibits ALL steps in the viral life Condylomata acuminate
cycle from fusion to release
2. With IMMUNOMODULATING and Hepatitis C
ANTI-PROLIFERATIVE EFFECTS
ANTI-HEPATITIS AGENTS
ANTI-HBV & ANTI-HCV AGENTS
INDICATIONS
Activity against both Hepatitis B and
PKNX TOXICITIES/ADRs
ROA: Parenteral (IV,IM,SQ) Nephrotoxic
Excretion: Renal clearance
Contraindications:
− Hepatic decompensation (acute
liver failure)
− Autoimmune disease (because it
is an immunomodulatory agent)
− Cardiac arrhythmia
− Pregnancy
Advantages:
− Half-life is longer
− More stable concentration in the
blood thus may be given once
per week
− Has the same efficacy as
Interferon Alfa, just more
convenient to use

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ANTI-HBV AGENTS only

Nucleotide/Nucleoside analogues 1. Main MOA: Inhibit HBV DNA (Chronic) Hepatitis B cannot be cured. It can only be controlled. But it will require lifetime treatment.
ADEFOVIR polymerase and inhibit nucleic acid
− Least likely to induce synthesis Goal: HBe Ag seroconversion
Hbe Ag seroconversion 2. Lower HBV DNA to undetectable − If a patient is HBe Ag(+), that patient is infectious
(weakest) levels (they are not eradicated, − We make the patient less infectious by giving antivirals
TENOFOVIR they are just controlled)
TELBIVUDINE 3. Reduce transaminase levels ADEFOVIR, TENOFOVIR, and LAMIVUDINE also have anti-HIV properties
LAMIVUDINE
ENTECAVIR
ANTI-HCV AGENTS only
1. Primary Goal: Viral eradication – absence of detectable viremia for 6 months after completion of treatment
2. Standard Treatment: Combination of once weekly Pegylated interferon plus daily oral Ribavirin
Nucleoside analogue Inhibits nucleic acid synthesis by Can also be used against: ROA: Oral Contraindications:
RIBAVIRIN blocking RNA-dependent DNA − HCV (oral) Absorption: not affected by food − Hemolytic anemia
polymerase − Respiratory Syncytial Virus Excretion: Renal clearance − End-stage renal disease
(RSV) given as aerosol Advantages: − Ischemic vascular disease
through nebulization) − Safer − Pregnancy
− Influenza − Fewer drug interactions
− HIV-1 − Given orally
Direct-acting antiviral drugs
(DAAs)
1. Protease inhibitors (-previr) NS3/4A protease inhibitor Problem: Very expensive
BOCEPREVIR
TELAPREVIR
SIMEPREVIR
2. NS5A inhibitors (-asvir) NS5A inhibitor
LEDIPASVIR
OMBITASVIR
DACLASTAVIR

3. Polymerase inhibitors (-buvir) NS5B polymerase inhibitor

Nucleoside analogue:
SOFOSBUVIR
Non-nucleoside analogues:
DASABUVIR
BECLABUBVIR

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ANTIVIRALS AGAINST RESPIRATORY INFECTIONS

DRUG MOA INDICATIONS PKNX TOXICITIES/ADRs
Neuraminidase inhibitors Neuraminidase Active against both Influenza A ZANAMIVIR
ZANAMIVIR − Enzyme that will facilitate and B and currently active against − Via inhalation (intranasal)
OSELTAMIVIR the release of infectious both H3N2 and H1N1 strains OSELTAMIVIR
PERAMIVIR virions or viral copies from − A prodrug used orally,
LANINAMIVIR infected cells Can also be used as prophylaxis activated in the gut and the
− Enzyme that will facilitate liver
the attachment of virus to PERAMIVIR
other cell receptors − Given IV

MOA: Golden Period: 48 hours

Prevent release of infectious virions and Best time to give these agents is within
inhibit their attachment to other cells 48 hours from the start of signs and
symptoms. They will lessen the
duration and severity of the illness. If
you give these agents more than 48
hours after, they will not have an effect
anymore.
Adamantanes Inhibit the uncoating of viral RNA Only active against Influenza A Oral
AMANTADINE within infected cells − Inhibit an early step in
RIMANTADINE replication of the Influenza A
but not Influenza B
Not used anymore due to high
resistance

OTHER ANTIVIRAL DRUGS

DRUG MOA INDICATIONS PKNX TOXICITIES/ADRs AND REMEDIES
PALIVIZUMAB Directed against the F surface protein Prevents RSV infections in high-risk
Humanized monoclonal antibody (glycoprotein) of the Respiratory infants
Syncytial Virus (RSV)
Also inhibits viral entry

IMIQUIMOD Immune response modifier Treatment of genital and perianal warts Topical
No effect on viral cycle Active against HPV

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II. ANTIVIRALS: MECHANISMS OF ACTION

SUMMARY
BLOCKS FUSION PREVENTS UNCOATING INHIBITS NUCLEIC ACID PREVENTS INTEGRATION INHIBITS RELEASE
SYNTHESIS
ENFUVIRTIDE and MARAVIROC ADAMANTANES against Influenza A Most of the antivirals INSTIs for HIV PROTEASE INHIBITORS inhibits
for HIV formation and release of mature virions
DOCOSANOL for HSV
PALIVIZUMAB for RSV NEURAMINIDASE INHIBITORS for
Influenza A and B
INTERFERON ALFA blocks all of these

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