Antiviral Agents

Janet Wong, M.D.

Antiviral Agents
Respiratory viruses

Herpesviruses

HIV

Amantadine

Acyclovir

Zidovudine

Rimantadine

Famciclovir

Didanosine

Ribavirin

Valacyclovir

Zalcitabine

Ganciclovir

Stavudine

Foscarnet

Lamivudine

Cidofovir

Nevirapine

Vidarabine

Saquinavir

Trifluridine

Indinavir
Ritonavir
Nelfinavir
Delavirdine

Amantadine/rimantadine -- Mechanism of

Amantadine and rimantadine have what is called an adamantyl cage

Action

membrane protein M2 is responsible for a transmembrane protein transport

structure. When the virus is endocytize into the cell, the influenza A

which increases the acidity inside of the cell and allows encoding. Both the
adamantyl cage structure of amantadine and rimantadine interferes with

adamantyl case structure interferes with transmembrane proton (H+)

can't be encoding of the virus. So, that is how these agents interfere with

transport initiated by influenza A membrane protein M2

the influenza A virus replication. Blockage of the hydrogen ion channel

blockage of H+ channel reduces intracellular acidification necessary

reduces intracellular acidification which is necessary for fusion of the

for fusion of influenza A to host cell endosomal membranes and

release of rind RNA

this transmembrane protein hydrogen ion transport and, therefore, there

influenza A to the host cell endosomal membranes and release of viral

RNA. Influenza B lacks the M2 protein and therefore influenza B is not
inhibited by either amantadine or rimantadine.

influenza B lacks M2 protein; not inhibited by either amantadine or

rimantadine

Amantadine/rimantadine -- Indications
Indications for amantadine and rimantadine. Prophylaxis of influenza A as

Prophylaxis of influenza A
Treatment of influenza A
- efficacy greatest if given within 48 hours of onset of symptoms
- rimantadine does not have FDA indication for treatment in children

well as treatment of influenza A. Now, for treatment of influenza A, efficacy

is greatest if the medications are given within 48 hours from the onset of
symptoms. Rimantadine does not have FDA indication for treatment in
children. However, it is equally efficacious with amantadine. I would have
no problems with using rimantadine in children for treatment if I was going
to use the medication because it is certainly much safer than amantadine.

Amantadine/rimantadine -- Adverse Events

Adverse events. Amantadine. They are very similar to the antihistamines.

Amantadine - similar to antihistamines

nervousness. Sometimes, particularly people who take anticholinergic

- nausea and vomiting

drugs in addition will end up with hallucinations and nightmares and a

- difficulty concentrating

number of CNS complications. With rimantadine, all adverse events are

- drowsiness

rare. The most common ones are nausea and vomiting. But actually as

- nervousness

and are pretty much equally distributed between the rimantadine recipients

Rimantadine - all adverse events are rare

and the placebo recipients. So, it does seem to be a pretty safe medication.

- nausea and vomiting

They include nausea and vomiting, difficulty concentrating, drowsiness,

you'll see in controlled trials the frequency of adverse events of all types

Both of these medications, however, can induce seizures in individuals who

have prior seizure disorder. In nursing homes this may be a problem, but

Both agents may induce seizures in individuals with prior seizure

it isn't usually a big problem for children. The medication can induce

disorder

seizures in an individual with a prior history of seizures.

Amantadine/rimantadine -- Resistance
Resistance. In general, epidemic strains are usually sensitive to these two
medications. The new strains that come up are almost always sensitive to

Epidemic strains are usually sensitive

Resistance occurs frequently during therapy. Resistance is due to single

resistance will develop frequently in the patient during therapy. If they

amino acid mutation of influenza A M2 protein

develop resistant virus or if they don't develop resistant virus, it does not

Cross resistance is expected

Resistant strains may be transmitted

these two medications. However, once you start using these medications,

affect their clinical outcome. The development of resistance on therapy

does not seem to interfere with the beneficial effect of the medication, and
it probably is a later phenomenon that occurs after the immune system has
already had enough time to start working on clearance of virus. However,
the resistant strains can be transmitted. The resistance occurs by a single
amino acid mutation of the influenza A M2 protein. Cross-resistance
between amantadine and rimantadine is to be expected.

Amantadine/rimantadine--Indications for Prophylaxis

The indications for prophylaxis. Immunization with an appropriate influenza

vaccine is the prevention method of choice. This method of choice may not
be adequate when the circulating strain is not in the vaccine you may want

Immunization with appropriate influenza vaccine is the prevention

to consider chemoprophylaxis. You may want to give rimantadine or

amantadine simultaneously to the vaccine if the vaccine is delayed until the

method of choice

influenza A outbreak has occurred. This is particularly relevant if you have

Amantadine/rimantadine indications:

a child who currently now is receiving the vaccine that could lead for the

(1) when circulating strain is not in vaccine

(2) to be given simultaneously with vaccine, if vaccine is delayed until
start of influenza A outbreak
(3) during an outbreak in institutions or hospitals which have children at
risk who can't take the vaccine (e.g. anaphylaxis to egg protein; age
<6 months)

first set of vaccines two doses four weeks apart. If you delayed it until the
onset of the epidemic, you may need to do it with the amantadine and
rimantadine for actually the entire six weeks because it will take four weeks
to get the vaccines in and it takes about two weeks after the second dose
to have an adequate immune response. So, if the vaccine was delayed, you
can use the chemoprophylaxis.

Another indication for prophylaxis would be during an outbreak in institutions or hospitals, or in home settings in which the child at risk for influenza
related complications (children who have bronchopulmonary dysplasia or
cystic fibrosis). If you have a child who can't take the vaccine, because they
have anaphylaxis to egg protein or their age is less than six months, you
may want to prophylax the individuals around that person in order to try to
reduce the amount of disease. Another situation where prophylaxis would
be indicated is if you have a child who comes to your office who has
influenza and they happen to have a sibling who is at risk for influenza
related complications. It is better to prophylax the family members so that
you can protect the at-risk child, because in general, most of the time,
influenza is going to be a relatively benign disease for the healthy child and
what you are trying to do is prevent disease in the child at risk.

Ribavirin--mechanism of Action
The mechanism of action for this particular agent is still unknown. It works

Unknown; may vary from viral species to viral species

Synthetic nucleoside analogue of guanosine or xanthosine

Other possible uses

Influenza A (aerosol)

Influenza B (aerosol)

Measles (intravenous; oral or aerosol)

Hemorrhagic fevers (intravenous)

kind of like a broad spectrum antiviral agent and it may actually work in
different ways for different viral species. It is a synthetic nucleoside
analogue of guanosine or xanthosine.

Ribavirin--indications
Indications. The major indication is for RSV lower respiratory tract

RSV lower respiratory tract infections in selected populations (aerosol)

Lassa fever (intravenous)

infections in selected populations and it is given by aerosol. It is also

indicated for Lassa fever given intravenously. Ribavirin is effective against
both influenza A and influenza B, and, in some studies, it looks like it has
clinical efficacy for treatment of influenza A and B. There have been
anecdotal reports of success using intravenous, oral or aerosol ribavirin for
the treatment of measles infection. Most of this is noncontrolled, so true
efficacy and safety is not really clear.

Ribavirin--indications for Treatment of RSV

Infection

The one area where ribavirin is most commonly considered for use is for
treatment of RSV infections. Right now, ribavirin may be considered for
children with RSV infection in a number of specific problems: complicated

Ribavirin may be considered for children with:

congenital heart disease, particularly those that have high pulmonary artery
pressures; underlying lung disease, especially bronchopulmonary dysplasia

complicated congenital heart disease

and cystic fibrosis; prematurity with a gestation of less than 37 weeks;

underlying lung disease, especially bronchopulmonary dysplasia and

infants who are less than six weeks of age who develop their RSV lower

cystic fibrosis

respiratory tract disease; children who are immunocompromised; severely

ill infants, those who have high oxygen requirements or mechanical

prematurity (<37 weeks gestation)

infants <6 weeks of age

children who are immunocompromised

severely ill infants (e.g. high oxygen requirements; mechanical

been supported by some of the newer studies. There is a major concern

ventilation)

that patients who are on mechanical ventilation actually do poorer if they

certain chronic, debilitating conditions

receive ribavirin than patients who receive the placebo, and the hospitaliza-

ventilation and certain chronic debilitating conditions.

Ribavirin may actually have an antiviral effect, and there may even be some
benefit but the clinical benefit, that was discussed in earlier papers hasn't

tions were more prolonged. The medication may have a role, but we still
have to figure out exactly what that role is. In certain populations at highest
risk for RSV complications, I think it can be considered.

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Ribavirin Adverse Events

Adverse events. It doesn't have a lot of adverse events. In the aerosol, they

Aerosol - rare; minimal systemic absorption

are rare. There is minimal systemic absorption. You can see

bronchospasms, rash, and conjunctivitis can seen (both in the patient and

bronchospasm

in the caretakers). You can see malfunction of the ventilator delivery

rash

system. Endotracheal tubes may be clogged as a result of deposition of

conjunctivitis

malfunction of ventilator delivery system

Systemic

ribavirin. Most of the ventilator related problems can be managed with

meticulous care. When given systemically, either oral or intravenously, you
can also see anemia and hyperbilirubinemia. Resistance has not yet been
identified. The use of this agent has been decreasing.

- oral or intravenous
- anemia
- hyperbilirubinemias
Ribavirin resistance has not yet been identified

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Acyclovir/valacyclovir
Anti-herpes antiviral agents. Valacyclovir together because valacyclovir is
the L-valyl ester of acyclovir. Acyclovir is a synthetic acyclic purine

acyclovir is a synthetic acyclic purine nucleoside analogue of guanosine

valacyclovir is L-valyl ester of acyclovir

acyclovir in that it is about three to five times more bioavailable. This fact

hydrolysis of valacyclovir to acyclovir occurs in the intestinal wall and

results in improvement in bioavailability.

nucleoside analogue of guanosine. Valacyclovir has one advantage over

liver

valacyclovir is 3-5 limes more bioavailable than acyclovir

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Acyclovir/valacyclovir -- Mechanism of Action

Mechanism of action. Acyclovir is catalyzed to the acyclovir monophosphate
by the herpes virus thymidine kinase. So, cells that are not infected with

acyclovir is catalyzed to acyclovir MP by herpes virus thymidine kinase

cellular kinases transform acyclovir MP to acyclovir triphosphate

acyclovir to the acyclovir monophosphate, so that active acyclovir, which is

(acyclo-GTP)

the acyclovir triphosphate, occurs much, much less commonly in unin-

acyclovir triphosphate

herpes simplex have about 100-1000 times less phosphorylation of

fected cells. The cellular kinases transform the monophosphate to the

triphosphate. Acyclovir does not have a three-pronged hydroxyl group and

DNA chain termination (lacks 3'-OH)

this three-pronged hydroxyl group is important for elongation of a forming

terminated DNA chains bind with viral DNA polymerase

DNA molecule. So, if you get incorporation of the acyclo-GTP into the DNA
chain, it will terminate. This terminated chain will turn around and bind with
DNA polymerase. So, that it actually creates chain termination and
inhibition of the DNA polymerase. That slows down replication of herpes
simplex and other herpes viruses.

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Acyclovir/valacyclovir Indications
Indications. It can be life saving and also can reduce the discomfort and
problems associated with those conditions. It also can be indicated for

Herpes simplex virus infections

varicella zoster virus infections, and it may sometimes be used for chicken
pox and for zoster.

encephalitis

recurrent genital gingivostomatitis

neonatal HSV

whitlow

first episode genital

eczema herpeticum

suppression of genital

prophylaxis of seropositive bone marrow

recurrences

transplant

recurrent genital
Varicella zoster virus
- chicken pox
-zoster (shingles)

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Acyclovir/valacyclovir
Acyclovir is available in a tablet, syrup, topical and intravenous. My

acyclovir (tablet; syrup; topical; and intravenous)

experience is that the topical probably doesn't have much of a role anymore
in use with therapy. If you need to use acyclovir, you should use one of the

valacyclovir (tablet)

systemic forms. Valacyclovir is available in a tablet. Therapy is likely to

therapy likely to yield greatest benefit:

yield

- primary infections

the

greatest

clinical

benefit

for

primary

infections

in

immunocompromised hosts if the dose is initiated very early in the disease.

Also, the dose required to treat varicella zoster virus infections is higher

- immunocompromised

than what we need for herpes simplex. The reason for that is if you look at

-initiated early

the range of sensitivity in the different agents, you can see that the amount

dose required for VZV > HSV

of acyclovir that is required to inhibit herpes simplex virus is approximately

two to four times lower than with the varicella zoster virus.

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Acyclovir -- Antiviral Spectrum

You can see that the Epstein-Barr virus is inhibited somewhat and that the
cytomegalovirus doesn't seem to be very sensitive. Both the Epstein-Barr
virus and the cytomegalovirus lack the viral thymidine kinase that is
required for phosphorylating the acyclovir to the acyclovir monophosphate.
That's the reason that those two viruses don't respond very well to

HSV 1

0.02-0.2 ug/mL

most sensitive

HSV 2

0.03-0.5 ug/mL

2 told less sensitive

VZV

0.8-l.2 ug/mL

needs higher dose than HSV

EBV

1.6 ug/mL

no viral thymidine kinase

CMV

> 22 ug/mL

no viral thymidine; resistant

treatment with acyclovir.

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Acyclovir/valacyclovir -- Adverse Events

Adverse events with acyclovir and valacyclovir. Increased BUN and
creatinine, nausea and vomiting, diarrhea, itching, rash, vertigo, arthralgia,

increased BUN/creatinine

vertigo

nausea/vomiting

arthralgia

that common but they can occur. With intravenous you will get a much

diarrhea

fever

higher level and you sometimes can get inflammation or phlebitis at the

itching

headache

fever, headache. These are all reported. In general, most of them are not

injection site. You can get precipitation of acyclovir crystals in the renal
tubules and this can be prevented by a one hour infusion and by ensuring

rash

adequate hydration. Encephalopathic changes of lethargy, obtundation,

intravenous

tremor have been seen. Two of the risks would be patients who have had
prior neurologic disease, child herpes simplex encephalitis, or some other

inflammation or phlebitis at injection site

precipitation of acyclovir crystals in renal tubules (prevented by

then get markedly elevated levels of acyclovir because acyclovir is renally

1 hour infusion time and ensuring adequate hydration)

excreted. Patients who have recent hypoxia or those who are receiving

encephalopathic changes of lethargy, obtundation, tremor (risk is

methotrexate also are at increased risk for the encephalopathic changes.

condition of neurologic disease, or patients who have renal disease who

increased by prior neurologic or renal disease)

One of the things that has been seen with valacyclovir but not in acyclovir
has been thrombotic thrombocytopenic purpura or hemolytic uremic

Thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome

syndrome. It has been noted only in severely immunocompromised patients

has been noted in a few severely immunocompromised patients

receiving valacyclovir. It seems to be rare, but it certainly can be very life

receiving valacyclovir.

threatening.

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Acyclovir/valacyclovir -- Resistance
Resistance. There are a couple of ways that viruses can become resistant
to acyclovir and valacyclovir. The most common mechanism would be

thymidine kinase deficient mutants

alteration of either viral thymidine kinase or viral DNA polymerase

that has a mutation where it loses the thymidine kinase, it will no longer

Risk factors

phosphorylate acyclovir to acyclovir monophosphate. There can also be

- prolonged exposure

viruses that have alterations of either the viral thymidine kinase or the viral

- immunocompromised state

DNA polymerase and if those occur, and those occur much less commonly,
the virus also will be resistant then to acyclovir and valacyclovir.

If initial virus is acyclovir sensitive, reactivated latent virus will usually

have same susceptibility to acyclovir as initial strain

thymidine kinase deficient mutants. So, if you have a herpes simplex virus

Foscarnet (or cidofovir can be used for acyclovir-resistant HSV/VZV

Factors that increase the likelihood of resistance. Resistance after

prolonged exposure hasnt been as common with suppression of genital
herpes, but resistance is more common after prolonged exposure in
immunocompromised patients. In that set of circumstances, you've got a
situation where you have large quantities of virus replicating with prolonged
exposure to the antiviral agent and that seems to markedly increase the risk
for development of resistance. If the initial virus is acyclovir sensitive,
reactivated latent virus will usually have the same susceptibility to acyclovir
as the initial strain. The next time that they have an outbreak, that virus very
likely will still be acyclovir sensitive because the latent virus hasn't been
affected by being exposed to therapy. Medications that you can use for
acyclovir resistant virus include both foscarnet or cidofovir.

18

Famciclovir
Famciclovir. This is also a synthetic acyclic guanine derivative. It is a prodrug of penciclovir. Penciclovir is phosphorylated to penciclovir

synthetic acyclic guanine derivative

pro-drug of penciclovir (famciclovir is converted to penciclovir)

happens with acyclovir. The indications, adverse events and resistance

penciclovir is phosphorylated to penciclovir monophosphate by viral

issues are pretty similar for famciclovir and acyclovir.

monophosphate by the viral thymidine kinase. So, it is very similar to what

thymidine kinase

indications, adverse events, and resistance issues are similar as for

famciclovir and acyclovir

19

Foscarnet Mechanism of Action

Foscarnet. Foscarnet is the analogue of pyrophosphate. It selectively

organic analogue of inorganic pyrophosphate

inhibits at the pyrophosphate binding site of the viral DNA polymerase and
the reverse transcriptase of HIV at concentrations that do not affect cellular

selectively inhibits at pyrophosphate binding site of viral DNA

DNA polymerase. When the pyrophosphate binding site is blocked, it

polymerase and reverse transcriptase at concentrations that do not

interferes with removal of phosphate groups that are important for gene

affect cellular DNA

linking, preventing elongation of the DNA chains. But it works in an entirely

different mechanism from acyclovir and valacyclovir. If you have certain

prevents elongation of DNA chains

mutations, either thymidine kinase or viral DNA polymerase, that would

does not require viral thymidine kinase

make the virus resistant to acyclovir it may still be sensitive to foscarnet.

Indications
Indications. The primary ones right now are CMV retinitis in AIDS patients

1. CMV retinitis in AIDS

and

2. acyclovir-resistant HSV in immunocompromised hosts

immunocompromised hosts. In AIDS patients with CMV retinitis, ganciclovir

acyclovir

resistant

herpes

simplex

virus

infections

in

and foscarnet are fairly similar. However, the patients who received
foscarnet had a slightly greater survival time. Foscarnet is more toxic and
more difficult to deliver. For CMV retinitis in AIDS patient, foscarnet would
be an alternative to ganciclovir; however, there was a slight survival benefit
in the foscarnet recipients as compared to the ganciclovir recipient.

20

Foscarnet -- Adverse Events

Adverse events. Foscarnet is a much more nephrotoxic medication than
ganciclovir. It also causes a lot of changes in some of the minerals and

increased BUN/creatinine

nausea

hypocalcemia (total or ionized)

anemia

also receiving pentamidine. It results in an increase or decrease in

hyper or hypophosphatemia

diarrhea

phosphorus levels, a decrease in magnesium, and an increase in

hypomagnesemia

seizures

hyperkalemia

granulocytopenia

are also penile or vulvar ulcerations. Urination of this medication can cause

fever

penile/vulvar ulcerations

ulcerations. So, in order to reduce that, the person should be very well

electrolytes resulting in decreased calcium. This is exacerbated in patients

potassium. You can get fever, nausea, anemia. The anemia is worse if
you're receiving zidovudine. Diarrhea, seizures, granulocytopenia. There

hydrated or else they will have the ulcerations and burning.

21

Foscarnet -- Precautions
Precautions. If you use nephrotoxic agents, you can have increased

nephrotoxic agents cause increased nephrotoxicity

nephrotoxicity like patients on aminoglycosides, pentamidine. Pentamidine

increases the chance for hypocalcemia. Phlebitis is very common and you

IV pentamidine causes hypocalcemia

want to get it in a large vein with a good blood flow so you don't end up with

phlebitis common

problems of phlebitis. Foscarnet affects the development of tooth enamel

foscarnet affects development of tooth enamel and bones in mice and

and bones in developing mice and rats. We don't know anything about how

rats (possibly children)

this affects tooth enamel and bone development in children. Foscarnet may
have a role in children, but we need to be cautious.

22

Foscarnet Resistance
Resistance. The primary mechanism for resistance is mutations in the viral

mutations in viral DNA polymerase

cross-resistance with other antiviral agents is common

DNA polymerase that change the pyrophosphate binding site. If you have
a mutation in the viral DNA polymerase that makes the virus resistant to
foscarnet, it is not unusual for it to have cross-resistance with the acyclovir
group of medications as well.

23

Ganciclovir -- Mechanism of Action

Ganciclovir is a medication that was recognized to be valuable for CMV.

ganciclovir is transformed to ganciclovir MP by enzyme phosphono

transferase that is encoded by UL-97 gene of CMV
inhibits CMV replication
-

CMV DNA chain termination

competitive inhibition of CMV DNA polymerase

The reason is that it is transformed to its more active monophosphate form

by an enzyme phosphotransferase that is encoded by a gene of CMV. It
causes chain termination and inhibition of CMV DNA polymerase as does
acyclovir.

24

Ganciclovir -- Indications
Indications. Treatment and prophylaxis of CMV retinitis. It may also be use

CMV retinitis

for CMV colitis, CMV esophagitis, CMV pneumonitis. With CMV pneumonitis, if you are going to treat a bone marrow transplant patient or another

Treatment

similarly immunocompromised patient, you may want to consider using

Prophylaxis

CMV hyperimmune globulin along with it. Because in the bone marrow

CMV colitis
CMV esophagitis
CMV pneumonitis

transplant patient, the ganciclovir alone did not have significant benefit but
the combination seemed to have a benefit. Again, we've got the question
mark for congenital CMV. It may have a role for treating active disease. It
is not likely to be able to reverse damage that has already occurred, and we
may actually find that when we look at the risks of this medication and the
benefits, that it may actually have a role for protecting the development of
symptoms that occur with congenital disease.

25

Ganciclovir -- Adverse Events

Adverse effects. Ganciclovir does have adverse effects that are common.
Most of the time you can treat through them. It does have a significant effect

granulocytopenia

elevated LFT

thrombocytopenia

headache

receiving other medications that are affecting the bone marrow like

anemia

confusion

zidovudine. Granulocytopenia and thrombocytopenia and anemia. You get

fever

increased BUN/creatinine

rash

nausea/vomiting/anorexia

on bone marrow. This is also something that is exacerbated in patients

fever, rashes, mild increases in the LFT, headache, confusion. It has some
mild effects on the kidney and it also may cause some GI problems with
nausea, vomiting and anorexia.

26

Ganciclovir -- Precautions
Precautions. Therapy in immunocompromised patients usually requires

therapy in immunocompromised patients requires prolonged

prolonged maintenance therapy. In HIV infected patients, it is lifelong.

Fortunately, there now is both an intravenous and oral form. If you use other

maintenance therapy (life-long in HIV)

nephrotoxic drugs, you are going to have a much bigger problem with

nephrotoxic drugs cause increased nephrotoxicity

nephrotoxicity. The other thing is that it is carcinogenic in mice.

carcinogenic in mice

27

Ganciclovir -- Resistance
Resistance. If you use ganciclovir in an immunocompromised host for

relatively common during prolonged therapy Ca 8%)

associated with clinical disease progression

receiving it for retinitis, greater than 8% were resistant. Resistance is

2 mechanisms

associated with clinical disease progression, so that when you start seeing

- alteration of CMV phosphono transferase

- alteration of CMV DNA polymerase

ganciclovir-resistant CMV may be sensitive to foscarnet and cidofovir

prolonged periods of time, you are going to see resistance. In AIDS patients

resistance, you'll start seeing recurrence of the symptoms that were

present before the medication was started. There are two separate
mechanisms. One is an alteration of the CMV phosphotransferase enzyme.
The other one is alteration of the CMV DNA polymerase. Ganciclovir
resistant CMV may be sensitive to either foscarnet or cidofovir.

28

Cidofovir -- Mechanism of Action

Cidofovir is an acyclic nucleoside monophosphate derivative. Cidofovir is
phosphorylated to a diphosphate by host cell enzymes so it does not need

acyclic nucleoside monophosphate derivative

cidofovir is phosphorylated to diphosphate by host cell enzymes

competitive inhibitor for the normal substrate, deoxycytidine triphosphate,

inhibits viral DNA

causing chain termination. Cidofovir inhibits viral DNA polymerase at a

- competitive inhibitor (normal substrate d CTP

a viral encoded enzyme for phosphorylation. It inhibits viral DNA as a

concentration of 50-1000 fold less than cellular DNA polymerases.

- alternate substrate

cidofovir inhibits viral DNA polymerase at concentration 50-1000 fold

less than cellular DNA polymerase

29

Cidofovir -- Indications

CMV retinitis (intravenous or intravitreal)

acyclovir-resistant HSV

papillomatous lesions (intra-tumoral injection)

30

Cidofovir -- Spectrum of Activity

Herpes simplex virus (including acyclovir resistant)

Varicella-zoster virus

Cytomegalovirus (including ganciclovir and foscarnet -resistant)

Epstein-Barr Virus

31

Cidofovir -- Adverse Events

Adverse events. Cidofovir can cause neutropenia, peripheral neuropathy

neutropenia

and nephrotoxicity. The nephrotoxicity can be considerable and actually is

very commonly the limiting factor for this medication. It is a proximal tubular

peripheral neuropathy

dysfunction and nephrotoxicity can be reduced by giving oral probenecid

nephrotoxicity (proximal tubular dysfunction)

plus prehydration with normal saline. Unfortunately, these measures will

Nephrotoxicity can be reduced by oral probenecid plus prehydration with

normal saline

not always prevent nephrotoxicity. Medication is usually given once a week

so sometimes you can give it every other week if you want to try to reduce
nephrotoxicity.

32

Cidofovir -- Resistance
not yet seen in treated patients
has occurred in vitro

Resistance. It has occurred in vitro. It has not yet been described in patients
who were treated. Since it has been described in vitro, it is likely to happen,
particularly if it gets used with any frequency in immunocompromised
patients.

33

Trifluridine -- Mechanism of Acton

Trifluridine. This is a medication that is primarily used topically for

inhibits thymidylic phosphorylase and specific DNA polymerase necessary

for incorporation of thymidine into viral DNA
incorporated into viral DNA resulting in faulty viral DNA

treatment of herpes keratoconjunctivitis. It inhibits the thymidine

phosphorylase and specific DNA polymerase necessary for incorporation
of thymidine into the viral DNA. Incorporating into the viral DNA results in
faulty viral DNA, which cannot grow any further into the replication cycle.

34

Trifluridine -- Indications
Indications include herpes simplex keratitis or herpes simplex

Herpes simplex keratitis

keratoconjunctivitis.

Herpes simplex keratoconjunctivitis

Adverse events. It can cause some local irritation and photophobia. You

Adverse Events

need to use it usually early in the therapy very frequently, every two to three

local irritation
photophobia

hours, and it may cause some edema of the eyelids or the cornea.
Superficial punctate keratopathy and increased intraocular pressure are
pretty rare. Resistance has not yet been documented.

edema of eyelids and cornea

superficial punctate keratopathy
increased intraocular pressure
Resistance has not yet documented

35

Antiretroviral Agents
Antiretroviral agents. Medications that are available include the nucleoside

Nucleoside reverse transcriptase inhibitors

reverse transcriptase inhibitors, the non-nucleoside reverse transcriptase

inhibitors, and the protease inhibitors.

Non-nucleoside reverse transcriptase inhibitors

Protease inhibitors

36

Antiretroviral Agents Nucleoside RT Inhibitors

For the nucleoside reverse transcriptase inhibitors, we have the original

medication zidovudine or AZT, didanosine or ddI, zalcitabine or ddC,
stavudine or d4T and lamivudine 3TC. Monotherapy with any of these

Zidovudine (AZT or ZDV)

agents would not be considered optimal.

Didanosine (ddI)

Zalcitabine (ddC)

Stavudine (d4T)

Lamivudine (3TC)

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Nucleoside Rt Inhibitors -- Mechanism of Action

These agents are phosphorylated to triphosphate by cellular enzymes and

they work intracellularly. Triphosphate is incorporated into the viral DNA
resulting in chain termination.

phosphorylated to triphosphate by cellular enzymes

triphosphate incorporated into viral DNA causing chain termination

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Nucleoside RT Inhibitors -- Adverse Events

Adverse events. Zidovudine causes multiple adverse events, which are

Zidovudine - hematologic, nausea:, hepatotoxicity

relatively common. Most of them, however, are not life threatening or

serious. Anemia and neutropenia are very common. Nausea and some

Didanosine - pancreatitis; neuropathy; diarrhea

hepatotoxicity. I think we are now starting to learn that with zidovudine you

Zalcitabine - neuropathy, pancreatitis

can probably live with a lower neutrophil count than you were happy with

Stavudine - neuropathy, pancreatitis

before. It is a relatively safe medication but not everyone can tolerate it.

Lamivudine - pancreatitis; hematologic

Didanosine. The major adverse effects that we worry about are pancreatitis, neuropathy and diarrhea. The diarrhea is caused by the buffer that is
included with the medication.
Zalcitabine. Neuropathy and pancreatitis.
Stavudine causes neuropathy and pancreatitis.
Lamivudine. Pancreatitis is a problem and then hematologic. Pancreatitis,
which is something that is seen not uncommon in adults, may occur in
children, but it doesn't seem to be a significant problem. In general, the
nucleoside reverse transcriptase inhibitors are relatively well tolerated and
probably out of all of them, zidovudine is the one with the greatest
concerns.

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Nucleoside RT Inhibitors -- Resistance

Resistance. Resistance occurs following mutations of the viral reverse

occurs following mutations of viral reverse transcriptase

likelihood of developing resistance related to:
disease state (symptomatic > asymptomatic)
viral load (higher replication)
combination therapy may prolong time to development of resistance

transcriptase. Symptomatic children are more likely than asymptomatic

children to develop resistance. Probably this is a reflection of viral load
because of higher replication. Viral load is probably one of the key
indicators of how successful you are with your antiretroviral therapy.
Medications, such as zidovudine or didanosine, when used alone result in
such a small decrease in the viral load that there is so much viral replication still occurring, billions a day, that the expectation should be there that
you will develop resistance. So, for that reason, a combination of therapies
may prolong the time for development of resistance. Combination therapy
has to be adequate to reduce viral replication down to a point where
mutations are not likely to occur. Most people would feel most comfortable
with undetectable virus loads.

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Antiretroviral Agents Non-nucleoside RT

Inhibitors

We now have two non-nucleoside reverse transcriptase inhibitors,

nevirapine and delavirdine. No phosphorylation is required.

Nevirapine
Delavirdine

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Non-nucleoside RT Inhibitors -- Mechanism of

Action

They are noncompetitive inhibitors of reverse transcriptase by binding to

the reverse transcriptase at a site that is distinct from the substrate binding

structurally similar to benzodiazepines

site. So, they work with an entirely different mechanism than the nucleoside
reverse transcriptase inhibitors. When you look at potency of the antiviral

no phosphorylation required

effect of the non-nucleoside reverse transcriptase inhibitors, they seem to

non-competitive inhibitor of RT by binding to RT at site distinct from the

be greater in potency than the nucleoside reverse transcriptase inhibitors,

substrate binding site

but they are not as potent as protease inhibitors.

antiviral effect
- protease inhibitors > non-nucleoside RT inhibitors > nucleoside RT
inhibitors

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Nevirapine -- Adverse Events

Adverse events. Rash. It is relatively common in adults and maybe as many

rash including Stevens-Johnson Syndrome

as 3-5% of adults will go on to develop very severe rash including StevensJohnson syndrome. If you use these medications and step up in the dosing,

fever

you can sometimes reduce the incidence of the rash. You may also see

hematotoxicity

fever, hepatotoxicity or myalgia.

myalgia

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Non-nucleoside RT Inhibitors -- Resistance

Resistance with monotherapy for these agents occurs very rapidly. Actually,

resistance occurs rapidly with monotherapy

within a few weeks of monotherapy, you will develop resistance to these

agents. These are agents that can never be used in monotherapy. Even in

resistance occurs as a result of mutations in reverse transcriptase

situations where you have combination therapy, you have to be concerned

combination with other antiretroviral agents delays development of

about development of resistance if you don't have immunosuppression of

resistance

the virus. So, combination with other antiretroviral agents delays development of resistance but you really need to be very careful because if you
don't have suppression of replication, you are going to have problems.

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Antiretroviral Agents -- Protease Inhibitors

Protease inhibitors. Saquinavir, indinavir, ritonavir and nelfinavir. They work

Saquinavir
Indinavir

by binding to both HIV-1 and HIV-2 protease, rendering it incapable of

cleaving the viral polyprotein precursors into the individual structural
proteins necessary for assembly of new viral progeny.

Ritonavir
Nelfinavir

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Protease Inhibitors Mechanism of Action

Adverse events. Saquinavir causes nausea, diarrhea and confusion. There

Binds to both HIV-1 and HIV-2 protease rendering it incapable of cleaving

are now some soft gel preparations that may increase bioavailability and for
some older children who can swallow tablets, they may be an alternative.

viral polyproteins precursors into individual structural proteins necessary

Indinavir is only available as a tablet but children may be able to take this

for assembly of new viral progeny.

as young as age four or five. Nausea is not uncommon. Indirect

hyperbilirubinemia is an issue and this will be an issue particularly in young
infants and newborns. Kidney stones may occur in more than 5%. You
really need to hydrate the patient very well and this isnt always easy in
children.

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Protease Inhibitors -- Adverse Events

Ritonavir may cause nausea and vomiting. It is a very difficult medication

Saquinavir - nausea, diarrhea, confusion

to get patients to tolerate. You need to give it with chocolate milk or peanut
butter or something. Circumoral paresthesia, taste perversion. It is not the

Indinavir - nausea; kidney stones, direct hyperbilirubinemia

best of the medications but it does have a very good antiviral effect.

Ritonavir- nausea; vomiting, circumoral paresthesia; taste perversion

Nelfinavir is the medication of choice of the protease inhibitors for children

Nelfinavir - diarrhea

based on the fact that it has the greatest palatability and tolerability. Its
major side effect is diarrhea. There are some concerns that nelfinavir may
not be as potent as some of the other ones but that remains to be seen.

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Protease Inhibitors -- Resistance

Resistance occurs following mutations in the viral protease and cross-

resistance occurs following mutations in viral Prozac

cross resistance is common

resistance is common. If you use the protease inhibitors inappropriately,

then you can develop resistance and it may make it difficult to use any of
the other agents in that same class.

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Protease Inhibitors -- Drug Interactions

protease inhibitors inhibit cytochrome P450 activity causing increased

plasma levels of drugs metabolized by cytochrome P450

protease inhibitors increase activity of glucuronyl transferase causing

decreased plasma levels of drugs metabolized by glucuronyl transferase

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