Antiviral Agents

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Antiviral Agents
Janet Wong, M.D.

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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

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Amantadine/rimantadine -- Mechanism of
Action
adamantyl case structure interferes with transmembrane proton (H+)
transport initiated by influenza A membrane protein M2
blockage of H+ channel reduces intracellular acidification necessary
for fusion of influenza A to host cell endosomal membranes and
release of rind RNA
influenza B lacks M2 protein; not inhibited by either amantadine or
rimantadine
Amantadine and rimantadine have what is called an adamantyl cage
structure. When the virus is endocytize into the cell, the influenza A
membrane protein M2 is responsible for a transmembrane protein transport
which increases the acidity inside of the cell and allows encoding. Both the
adamantyl cage structure of amantadine and rimantadine interferes with
this transmembrane protein hydrogen ion transport and, therefore, there
can't be encoding of the virus. So, that is how these agents interfere with
the influenza A virus replication. Blockage of the hydrogen ion channel
reduces intracellular acidification which is necessary for fusion of the
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.

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

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Amantadine/rimantadine -- Adverse Events
. Amantadine - similar to antihistamines
nausea and vomiting
- difficulty concentrating
drowsiness
- nervousness
. Rimantadine - all adverse events are rare
- nausea and vomiting
. Both agents may induce seizures in individuals with prior seizure
disorder
Adverse events. Amantadine. They are very similar to the antihistamines.
They include nausea and vomiting, difficulty concentrating, drowsiness,
nervousness. Sometimes, particularly people who take anticholinergic
drugs in addition will end up with hallucinations and nightmares and a
number of CNS complications. With rimantadine, all adverse events are
rare. The most common ones are nausea and vomiting. But actually as
you'll see in controlled trials the frequency of adverse events of all types
and are pretty much equally distributed between the rimantadine recipients
and the placebo recipients. So, it does seem to be a pretty safe medication.
Both of these medications, however, can induce seizures in individuals who
have prior seizure disorder. In nursing homes this may be a problem, but
it isn't usually a big problem for children. The medication can induce
seizures in an individual with a prior history of seizures.

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Amantadine/rimantadine -- Resistance
. Epidemic strains are usually sensitive
. Resistance occurs frequently during therapy. Resistance is due to single
amino acid mutation of influenza A M2 protein
. Cross resistance is expected
. Resistant strains may be transmitted
Resistance. In general, epidemic strains are usually sensitive to these two
medications. The new strains that come up are almost always sensitive to
these two medications. However, once you start using these medications,
resistance will develop frequently in the patient during therapy. If they
develop resistant virus or if they don't develop resistant virus, it does not
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.

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Amantadine/rimantadine--Indications for Prophylaxis
. Immunization with appropriate influenza vaccine is the prevention
method of choice
. Amantadine/rimantadine indications:
(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)
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
to consider chemoprophylaxis. You may want to give rimantadine or
amantadine simultaneously to the vaccine if the vaccine is delayed until the
influenza A outbreak has occurred. This is particularly relevant if you have
a child who currently now is receiving the vaccine that could lead for the
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.

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

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Ribavirin--indications
. RSV lower respiratory tract infections in selected populations (aerosol)
. Lassa fever (intravenous)
Indications. The major indication is for RSV lower respiratory tract
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.

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Ribavirin--indications for Treatment of RSV
Infection
. Ribavirin may be considered for children with:
complicated congenital heart disease
underlying lung disease, especially bronchopulmonary dysplasia and
cystic fibrosis
prematurity (<37 weeks gestation)
infants <6 weeks of age
children who are immunocompromised
severely ill infants (e.g. high oxygen requirements; mechanical
ventilation)
certain chronic, debilitating conditions
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
congenital heart disease, particularly those that have high pulmonary artery
pressures; underlying lung disease, especially bronchopulmonary dysplasia
and cystic fibrosis; prematurity with a gestation of less than 37 weeks;
infants who are less than six weeks of age who develop their RSV lower
respiratory tract disease; children who are immunocompromised; severely
ill infants, those who have high oxygen requirements or mechanical
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
been supported by some of the newer studies. There is a major concern
that patients who are on mechanical ventilation actually do poorer if they
receive ribavirin than patients who receive the placebo, and the hospitalizations
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
• Aerosol - rare; minimal systemic absorption
bronchospasm
rash
conjunctivitis
malfunction of ventilator delivery system
• Systemic
- oral or intravenous
anemia
- hyperbilirubinemias
• Ribavirin resistance has not yet been identified
Adverse events. It doesn't have a lot of adverse events. In the aerosol, they
are rare. There is minimal systemic absorption. You can see
bronchospasms, rash, and conjunctivitis can seen (both in the patient and
in the caretakers). You can see malfunction of the ventilator delivery
system. Endotracheal tubes may be clogged as a result of deposition of
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.

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Acyclovir/valacyclovir
. acyclovir is a synthetic acyclic purine nucleoside analogue of guanosine
. valacyclovir is L-valyl ester of acyclovir
. hydrolysis of valacyclovir to acyclovir occurs in the intestinal wall and
liver
. valacyclovir is 3-5 limes more bioavailable than acyclovir
Anti-herpes antiviral agents. Valacyclovir together because valacyclovir is
the L-valyl ester of acyclovir. Acyclovir is a synthetic acyclic purine
nucleoside analogue of guanosine. Valacyclovir has one advantage over
acyclovir in that it is about three to five times more bioavailable. This fact
results in improvement in bioavailability.

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Acyclovir/valacyclovir -- Mechanism of Action
acyclovir is catalyzed to acyclovir MP by herpes virus thymidine kinase
cellular kinases transform acyclovir MP to acyclovir triphosphate
(acyclo-GTP)
acyclovir triphosphate
DNA chain termination (lacks 3'-OH)
terminated DNA chains bind with viral DNA polymerase
Mechanism of action. Acyclovir is catalyzed to the acyclovir monophosphate
by the herpes virus thymidine kinase. So, cells that are not infected with
herpes simplex have about 100-1000 times less phosphorylation of
acyclovir to the acyclovir monophosphate, so that active acyclovir, which is
the acyclovir triphosphate, occurs much, much less commonly in uninfected
cells. The cellular kinases transform the monophosphate to the
triphosphate. Acyclovir does not have a three-pronged hydroxyl group and
this three-pronged hydroxyl group is important for elongation of a forming
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
Herpes simplex virus infections
• 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)
Indications. It can be life saving and also can reduce the discomfort and
problems associated with those conditions. It also can be indicated for
varicella zoster virus infections, and it may sometimes be used for chicken
pox and for zoster.

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Acyclovir/valacyclovir
. acyclovir (tablet; syrup; topical; and intravenous)
. valacyclovir (tablet)
. therapy likely to yield greatest benefit:
primary infections
immunocompromised
-initiated early
. dose required for VZV > HSV
Acyclovir is available in a tablet, syrup, topical and intravenous. My
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
systemic forms. Valacyclovir is available in a tablet. Therapy is likely to
yield 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
than what we need for herpes simplex. The reason for that is if you look at
the range of sensitivity in the different agents, you can see that the amount
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
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
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
treatment with acyclovir.

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Acyclovir/valacyclovir -- Adverse Events
• increased BUN/creatinine • vertigo
• nausea/vomiting • arthralgia
• diarrhea • fever
• itching • headache
• rash
• intravenous
inflammation or phlebitis at injection site
precipitation of acyclovir crystals in renal tubules (prevented by
1 hour infusion time and ensuring adequate hydration)
encephalopathic changes of lethargy, obtundation, tremor (risk is
increased by prior neurologic or renal disease)
Thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome
has been noted in a few severely immunocompromised patients
receiving valacyclovir.
Adverse events with acyclovir and valacyclovir. Increased BUN and
creatinine, nausea and vomiting, diarrhea, itching, rash, vertigo, arthralgia,
fever, headache. These are all reported. In general, most of them are not
that common but they can occur. With intravenous you will get a much
higher level and you sometimes can get inflammation or phlebitis at the
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
adequate hydration. Encephalopathic changes of lethargy, obtundation,
tremor have been seen. Two of the risks would be patients who have had
prior neurologic disease, child herpes simplex encephalitis, or some other
condition of neurologic disease, or patients who have renal disease who
then get markedly elevated levels of acyclovir because acyclovir is renally
excreted. Patients who have recent hypoxia or those who are receiving
methotrexate also are at increased risk for the encephalopathic changes.
One of the things that has been seen with valacyclovir but not in acyclovir
has been thrombotic thrombocytopenic purpura or hemolytic uremic
syndrome. It has been noted only in severely immunocompromised patients
receiving valacyclovir. It seems to be rare, but it certainly can be very life
threatening.

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Acyclovir/valacyclovir -- Resistance
. thymidine kinase deficient mutants
. alteration of either viral thymidine kinase or viral DNA polymerase
. Risk factors
prolonged exposure
immunocompromised state
. If initial virus is acyclovir sensitive, reactivated latent virus will usually
have same susceptibility to acyclovir as initial strain
. Foscarnet (or cidofovir can be used for acyclovir-resistant HSV/VZV
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. So, if you have a herpes simplex virus
that has a mutation where it loses the thymidine kinase, it will no longer
phosphorylate acyclovir to acyclovir monophosphate. There can also be
viruses that have alterations of either the viral thymidine kinase or the viral
DNA polymerase and if those occur, and those occur much less commonly,
the virus also will be resistant then to acyclovir and valacyclovir.
Factors that increase the likelihood of resistance. Resistance after
prolonged exposure hasn’t 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.

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Famciclovir
synthetic acyclic guanine derivative
pro-drug of penciclovir (famciclovir is converted to penciclovir)
penciclovir is phosphorylated to penciclovir monophosphate by viral
thymidine kinase
indications, adverse events, and resistance issues are similar as for
famciclovir and acyclovir
Famciclovir. This is also a synthetic acyclic guanine derivative. It is a pro-
drug of penciclovir. Penciclovir is phosphorylated to penciclovir
monophosphate by the viral thymidine kinase. So, it is very similar to what
happens with acyclovir. The indications, adverse events and resistance
issues are pretty similar for famciclovir and acyclovir.

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Foscarnet Mechanism of Action
• organic analogue of inorganic pyrophosphate
selectively inhibits at pyrophosphate binding site of viral DNA
polymerase and reverse transcriptase at concentrations that do not
affect cellular DNA
prevents elongation of DNA chains
does not require viral thymidine kinase
Indications
1. CMV retinitis in AIDS
2. acyclovir-resistant HSV in immunocompromised hosts
Foscarnet. Foscarnet is the analogue of pyrophosphate. It selectively
inhibits at the pyrophosphate binding site of the viral DNA polymerase and
the reverse transcriptase of HIV at concentrations that do not affect cellular
DNA polymerase. When the pyrophosphate binding site is blocked, it
interferes with removal of phosphate groups that are important for gene
linking, preventing elongation of the DNA chains. But it works in an entirely
different mechanism from acyclovir and valacyclovir. If you have certain
mutations, either thymidine kinase or viral DNA polymerase, that would
make the virus resistant to acyclovir it may still be sensitive to foscarnet.
Indications. The primary ones right now are CMV retinitis in AIDS patients
and acyclovir resistant herpes simplex virus infections in
immunocompromised hosts. In AIDS patients with CMV retinitis, ganciclovir
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.

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Foscarnet -- Adverse Events
increased BUN/creatinine • nausea
hypocalcemia (total or ionized) • anemia
hyper or hypophosphatemia • diarrhea
hypomagnesemia • seizures
hyperkalemia • granulocytopenia
fever • penile/vulvar ulcerations
Adverse events. Foscarnet is a much more nephrotoxic medication than
ganciclovir. It also causes a lot of changes in some of the minerals and
electrolytes resulting in decreased calcium. This is exacerbated in patients
also receiving pentamidine. It results in an increase or decrease in
phosphorus levels, a decrease in magnesium, and an increase in
potassium. You can get fever, nausea, anemia. The anemia is worse if
you're receiving zidovudine. Diarrhea, seizures, granulocytopenia. There
are also penile or vulvar ulcerations. Urination of this medication can cause
ulcerations. So, in order to reduce that, the person should be very well
hydrated or else they will have the ulcerations and burning.

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Foscarnet -- Precautions
. nephrotoxic agents cause increased nephrotoxicity
. IV pentamidine causes hypocalcemia
. phlebitis common
. foscarnet affects development of tooth enamel and bones in mice and
rats (possibly children)
Precautions. If you use nephrotoxic agents, you can have increased
nephrotoxicity like patients on aminoglycosides, pentamidine. Pentamidine
increases the chance for hypocalcemia. Phlebitis is very common and you
want to get it in a large vein with a good blood flow so you don't end up with
problems of phlebitis. Foscarnet affects the development of tooth enamel
and bones in developing mice and rats. We don't know anything about how
this affects tooth enamel and bone development in children. Foscarnet may
have a role in children, but we need to be cautious.

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Foscarnet – Resistance
. mutations in viral DNA polymerase
. cross-resistance with other antiviral agents is common
Resistance. The primary mechanism for resistance is mutations in the viral
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.

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Ganciclovir -- Mechanism of Action
. 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
Ganciclovir is a medication that was recognized to be valuable for CMV.
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.

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Ganciclovir -- Indications
. CMV retinitis
Treatment
Prophylaxis
. CMV colitis
. CMV esophagitis
. CMV pneumonitis
Indications. Treatment and prophylaxis of CMV retinitis. It may also be use
for CMV colitis, CMV esophagitis, CMV pneumonitis. With CMV pneumonitis,
if you are going to treat a bone marrow transplant patient or another
similarly immunocompromised patient, you may want to consider using
CMV hyperimmune globulin along with it. Because in the bone marrow
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.

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Ganciclovir -- Adverse Events
• granulocytopenia • elevated LFT
• thrombocytopenia • headache
• anemia • confusion
•fever • increased BUN/creatinine
• rash • nausea/vomiting/anorexia
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
on bone marrow. This is also something that is exacerbated in patients
receiving other medications that are affecting the bone marrow like
zidovudine. Granulocytopenia and thrombocytopenia and anemia. You get
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.

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Ganciclovir -- Precautions
therapy in immunocompromised patients requires prolonged
maintenance therapy (life-long in HIV)
nephrotoxic drugs cause increased nephrotoxicity
carcinogenic in mice
Precautions. Therapy in immunocompromised patients usually requires
prolonged maintenance therapy. In HIV infected patients, it is lifelong.
Fortunately, there now is both an intravenous and oral form. If you use other
nephrotoxic drugs, you are going to have a much bigger problem with
nephrotoxicity. The other thing is that it is carcinogenic in mice.

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Ganciclovir -- Resistance
. relatively common during prolonged therapy Ca 8%)
. associated with clinical disease progression
. 2 mechanisms
- alteration of CMV phosphono transferase
- alteration of CMV DNA polymerase
. ganciclovir-resistant CMV may be sensitive to foscarnet and cidofovir
Resistance. If you use ganciclovir in an immunocompromised host for
prolonged periods of time, you are going to see resistance. In AIDS patients
receiving it for retinitis, greater than 8% were resistant. Resistance is
associated with clinical disease progression, so that when you start seeing
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.

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Cidofovir -- Mechanism of Action
. acyclic nucleoside monophosphate derivative
. cidofovir is phosphorylated to diphosphate by host cell enzymes
. inhibits viral DNA
- competitive inhibitor (normal substrate d CTP
- alternate substrate
. cidofovir inhibits viral DNA polymerase at concentration 50-1000 fold
less than cellular DNA polymerase
Cidofovir is an acyclic nucleoside monophosphate derivative. Cidofovir is
phosphorylated to a diphosphate by host cell enzymes so it does not need
a viral encoded enzyme for phosphorylation. It inhibits viral DNA as a
competitive inhibitor for the normal substrate, deoxycytidine triphosphate,
causing chain termination. Cidofovir inhibits viral DNA polymerase at a
concentration of 50-1000 fold less than cellular DNA polymerases.

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Cidofovir -- Indications
CMV retinitis (intravenous or intravitreal)
acyclovir-resistant HSV
papillomatous lesions (intra-tumoral injection)

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Cidofovir -- Spectrum of Activity
Herpes simplex virus (including acyclovir resistant)
Varicella-zoster virus
Cytomegalovirus (including ganciclovir and foscarnet -resistant)
Epstein-Barr Virus

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Cidofovir -- Adverse Events
neutropenia
peripheral neuropathy
nephrotoxicity (proximal tubular dysfunction)
Nephrotoxicity can be reduced by oral probenecid plus prehydration with
normal saline
Adverse events. Cidofovir can cause neutropenia, peripheral neuropathy
and nephrotoxicity. The nephrotoxicity can be considerable and actually is
very commonly the limiting factor for this medication. It is a proximal tubular
dysfunction and nephrotoxicity can be reduced by giving oral probenecid
plus prehydration with normal saline. Unfortunately, these measures will
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.

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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.

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Trifluridine -- Mechanism of Acton
. inhibits thymidylic phosphorylase and specific DNA polymerase necessary
for incorporation of thymidine into viral DNA
. incorporated into viral DNA resulting in faulty viral DNA
Trifluridine. This is a medication that is primarily used topically for
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.

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Trifluridine -- Indications
. Herpes simplex keratitis
. Herpes simplex keratoconjunctivitis
. Adverse Events
local irritation
photophobia
edema of eyelids and cornea
superficial punctate keratopathy
increased intraocular pressure
Resistance has not yet documented
Indications include herpes simplex keratitis or herpes simplex
keratoconjunctivitis.
Adverse events. It can cause some local irritation and photophobia. You
need to use it usually early in the therapy very frequently, every two to three
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.

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Antiretroviral Agents
. Nucleoside reverse transcriptase inhibitors
. Non-nucleoside reverse transcriptase inhibitors
. Protease inhibitors
Antiretroviral agents. Medications that are available include the nucleoside
reverse transcriptase inhibitors, the non-nucleoside reverse transcriptase
inhibitors, and the protease inhibitors.

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Antiretroviral Agents Nucleoside RT Inhibitors
Zidovudine (AZT or ZDV)
Didanosine (ddI)
Zalcitabine (ddC)
Stavudine (d4T)
Lamivudine (3TC)
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
agents would not be considered optimal.

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Nucleoside Rt Inhibitors -- Mechanism of Action
. phosphorylated to triphosphate by cellular enzymes
. triphosphate incorporated into viral DNA causing chain termination
These agents are phosphorylated to triphosphate by cellular enzymes and
they work intracellularly. Triphosphate is incorporated into the viral DNA
resulting in chain termination.

39
Nucleoside RT Inhibitors -- Adverse Events
. Zidovudine - hematologic, nausea:, hepatotoxicity
. Didanosine - pancreatitis; neuropathy; diarrhea
. Zalcitabine - neuropathy, pancreatitis
. Stavudine - neuropathy, pancreatitis
. Lamivudine - pancreatitis; hematologic
Adverse events. Zidovudine causes multiple adverse events, which are
relatively common. Most of them, however, are not life threatening or
serious. Anemia and neutropenia are very common. Nausea and some
hepatotoxicity. I think we are now starting to learn that with zidovudine you
can probably live with a lower neutrophil count than you were happy with
before. It is a relatively safe medication but not everyone can tolerate it.
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.

40
Nucleoside RT Inhibitors -- Resistance
. 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
Resistance. Resistance occurs following mutations of the viral reverse
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.

41
Antiretroviral Agents – Non-nucleoside RT
Inhibitors
..Nevirapine
..Delavirdine
We now have two non-nucleoside reverse transcriptase inhibitors,
nevirapine and delavirdine. No phosphorylation is required.

42
Non-nucleoside RT Inhibitors -- Mechanism of
Action
. structurally similar to benzodiazepines
. no phosphorylation required
. non-competitive inhibitor of RT by binding to RT at site distinct from the
substrate binding site
. antiviral effect
protease inhibitors > non-nucleoside RT inhibitors > nucleoside RT
inhibitors
They are noncompetitive inhibitors of reverse transcriptase by binding to
the reverse transcriptase at a site that is distinct from the substrate binding
site. So, they work with an entirely different mechanism than the nucleoside
reverse transcriptase inhibitors. When you look at potency of the antiviral
effect of the non-nucleoside reverse transcriptase inhibitors, they seem to
be greater in potency than the nucleoside reverse transcriptase inhibitors,
but they are not as potent as protease inhibitors.

43
Nevirapine -- Adverse Events
. rash including Stevens-Johnson Syndrome
. fever
. hematotoxicity
. myalgia
Adverse events. Rash. It is relatively common in adults and maybe as many
as 3-5% of adults will go on to develop very severe rash including Stevens-
Johnson syndrome. If you use these medications and step up in the dosing,
you can sometimes reduce the incidence of the rash. You may also see
fever, hepatotoxicity or myalgia.

44
Non-nucleoside RT Inhibitors -- Resistance
. resistance occurs rapidly with monotherapy
. resistance occurs as a result of mutations in reverse transcriptase
. combination with other antiretroviral agents delays development of
resistance
Resistance with monotherapy for these agents occurs very rapidly. Actually,
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
situations where you have combination therapy, you have to be concerned
about development of resistance if you don't have immunosuppression of
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.

45
Antiretroviral Agents -- Protease Inhibitors
. Saquinavir
. Indinavir
. Ritonavir
. Nelfinavir
Protease inhibitors. Saquinavir, indinavir, ritonavir and nelfinavir. They work
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.

46
Protease Inhibitors Mechanism of Action
. Binds to both HIV-1 and HIV-2 protease rendering it incapable of cleaving
viral polyproteins precursors into individual structural proteins necessary
for assembly of new viral progeny.
Adverse events. Saquinavir causes nausea, diarrhea and confusion. There
are now some soft gel preparations that may increase bioavailability and for
some older children who can swallow tablets, they may be an alternative.
Indinavir is only available as a tablet but children may be able to take this
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 isn’t always easy in
children.

47
Protease Inhibitors --Adverse Events
• Saquinavir - nausea, diarrhea, confusion
• Indinavir - nausea; kidney stones, direct hyperbilirubinemia
• Ritonavir- nausea; vomiting, circumoral paresthesia; taste perversion
• Nelfinavir - diarrhea
Ritonavir may cause nausea and vomiting. It is a very difficult medication
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
best of the medications but it does have a very good antiviral effect.
Nelfinavir is the medication of choice of the protease inhibitors for children
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.

48
Protease Inhibitors -- Resistance
. resistance occurs following mutations in viral Prozac
. cross resistance is common
Resistance occurs following mutations in the viral protease and cross-
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.

49
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