ANTIVIRAL AGENTS

Viruses are obligate intracellular parasites; their replication depends primarily on synthetic
processes of the host cell. Viral replication consists of several steps: (1) adsorption to and
penetration into susceptible host cells; (2) uncoating of viral nucleic acid; (3) synthesis of early,
regulatory proteins, eg, nucleic acid polymerases; (4) synthesis of RNA/ DNA; (5) synthesis of
late, structural proteins; (6) assembly (maturation) of viral particles; and (7) release from the
cell.
Antiviral agents can potentially target any of these steps. Most of the antiviral agents currently
available act on synthesis of purines and pyrimidines (step 4); reverse transcriptase inhibitors
block transcription of the HIV RNA genome into DNA, thereby preventing synthesis of viral
mRNA and protein. The protease inhibitors act on synthesis of late proteins and packaging
(steps 5 and 6). In this section drugs used in the treatment of herps, human immunodeficiency
virus and other antiviral agents will be discussed.
Antiherpes Agents
Acyclovir
Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms: competitive inhibition of
the viral DNA polymerase and by binding to the DNA template as an irreversible complex..
Acyclovir is available in oral, intravenous, and topical formulations. Acyclovir diffuses into most
tissues and body fluids to produce concentrations that are 50-100% of those in serum.
Cerebrospinal fluid concentrations are 50% of serum values.
Clinical Uses: Oral acyclovir is effective for treatment of primary infection and recurrences of
genital and labial herpes. Intravenous acyclovir is the treatment of choice for herpes simplex
encephalitis, neonatal HSV infection and for severe primary, recurrent HSV genital and labial
infections and for those who cannot ingest oral pills
Adverse Reactions: Acyclovir is generally well tolerated. Nausea, diarrhea, and headache have
occasionally been reported. IV infusion may be associated with renal insufficiency or neurologic
toxicity.
Ganciclovir
The activated compound competitively inhibits viral DNA polymerase, causing an unstable
complex, but does not result in chain termination. Ganciclovir has activity against CMV, HSV,
VZV, and EBV; its activity against CMV is up to 100 times greater than that of acyclovir.
Clinical Uses: Intravenous ganciclovir is indicated for the treatment of CMV retinitis in patients
with AIDS. The drug also reduces the incidence of symptomatic CMV disease if administered
before organ transplantation. Administration of intravenous ganciclovir to treat CMV
pneumonitis in immunocompromised patients is often beneficial, particularly in combination with
intravenous cytomegalovirus immunoglobulin. Intravenous ganciclovir has also been used to
treat CMV colitis and esophagitis.
Adverse Reactions: The most common side effect of treatment with ganciclovir is
myelosuppression, particularly neutropenia. Myelosuppression may be additive in patients
receiving both ganciclovir and zidovudine. Central nervous system toxicity (changes in mental
status, seizures) has been rarely reported.
Foscarnet
Foscarnet is an inorganic pyrophosphate compound that inhibits viral DNA polymerase, RNA
polymerase, or HIV reverse transcriptase directly. It has in vitro activity against HSV, VZV,
CMV, EBV, HHV-6, HBV, and HIV.
The drug is available in an intravenous formulation only. Cerebrospinal fluid concentrations are
approximately two-thirds of steady state serum concentrations. Clearance of foscarnet is
primarily by the kidney. The initial elimination half-life is 4-8 hours, followed by a prolonged
terminal elimination half-life of 3-4 days in patients with normal renal function.
Clinical Uses: Foscarnet is used for patients with CMV retinitis and acyclovir-resistant HSV
infection Foscarnet has also been used to treat CMV colitis and esophagitis and acyclovirresistant VZV infection.
Adverse Reactions: The potential adverse effects include renal insufficiency, hypocalcemia or
hypercalcemia, and hypo- or hyperphosphatemia. Genital ulcerations associated with foscarnet
therapy may be due to high levels of ionized drug in the urine. Central nervous system toxicities
include hallucinations, and seizures.
Idoxuridine
Idoxuridine (IDU, IUDR) is a substituted pyrimidine analog that was the first antiviral agent to be
approved. It is used topically in the treatment of herpes keratitis (0.1% solution), but because of
its lack of selectivity it is too toxic for systemic administration.
Vidarabine
Vidarabine as a 3% ointment is effective treatment for acute keratoconjunctivitis, superficial
keratitis, and recurrent epithelial keratitis due to HSV. Intravenous vidarabine (10-15 mg/kg
daily) is effective for treatment of HSV encephalitis, neonatal herpes, and VZV infection in
immunocompromised patients. The drug is eliminated primarily by renal mechanisms as the
hypoxanthine metabolite. Potential toxicities include gastrointestinal intolerance, neurologic
manifestations (confusion, myoclonus, seizures), and myelosuppression.
Antiretroviral Agents
Antiretroviral drugs are synthetic agents that have antiviral activity against HIV and are used in
the management of HIV infection. There are four different classes of antiretroviral agents
commercially available currently: Nucleoside reverse transcriptase inhibitors (NRTI), Protease
inhibitors, Nonnucleoside reverse transcriptase inhibitors (NNRTI), and Fusion inhibitors.
Reverse transcriptase inhibitors
Zidovudine
Zidovudine (AZT) is a deoxythymidine analog that requires anabolic phosphorylation for
activation to the 5′-triphosphate form. After entering the cell by passive diffusion, zidovudine is
phosphorylated via three cellular kinases; the triphosphate is a competitive inhibitor of
deoxythymidine triphosphate for the reverse transcriptase. Additionally, it acts as a chain
terminator in the synthesis of proviral DNA. Zidovudine has in vitro activity against HIV-1, HIV-2,
and the human T cell lymphotropic viruses.
Resistance: Zidovudine resistance is due to mutations in the reverse transcriptase gene and is
more frequent in persons with advanced HIV infection. Withdrawal of zidovudine exposure may
permit the reversion of HIV-1 isolates to the susceptible (wild-type) phenotype.
Pharmacokinetics: Zidovudine is available in intravenous and oral formulations. It is well
absorbed from the gut and distributed to most body tissues and fluids, including the
cerebrospinal fluid, where drug levels are approximately 60% of those in serum. Substantial
first-pass metabolism to an inactive glucuronidated metabolite results in a systemic
bioavailability of approximately 65%.
Clinical Uses: Zidovudine inhibits replication of HIV-1 in infected individuals and has been
shown to decrease the rate of clinical disease progression and prolong survival. Zidovudine has
efficacy in the treatment of HIV-associated encephalopathy and thrombocytopenia, and in the
prevention of vertical (mother to newborn) transmission of HIV. Clinical efficacy is limited by the
relatively rapid development of resistance, particularly when used as monotherapy.
Adverse Reactions: The most common adverse effect is myelosuppression gastrointestinal
intolerance, headaches, and insomnia may occur but tend to resolve if ingestion is continued.
Less frequent unwanted effects include thrombocytopenia, acute cholestatic hepatitis, and
myopathy.
Didanosine
Didanosine (ddI) is a synthetic analog of deoxyadenosine. It is metabolized intracellularly by a
series of cellular enzymes; its active moiety, 2,3-dideoxyadenosine-5-triphosphate, inhibits viral
replication by competitive inhibition of HIV reverse transcriptase and by chain termination.
Pharmacokinetics: Absorption is decreased by food. Cerebrospinal fluid concentrations of the
drug are approximately 20% of serum concentrations. The elimination half-life is 0.6-1.5 hours,
but the intracellular half-life of the activated compound is approximately 12 hours. The drug is
eliminated by glomerular filtration and tubular secretion.
Clinical Uses: Didanosine is effective in slowing clinical progression of disease in HIV-infected
individuals when administered as monotherapy or in combination with zidovudine. The dosage
should be reduced for low body weight.
Adverse Reactions: The major clinical toxicity associated with didanosine therapy is dosedependent pancreatitis. Other reported adverse effects have included peripheral neuropathy,
diarrhea, hepatotoxicity, hematocytopenias, and central nervous system toxicity (headache,
irritability). A rise in uric acid during therapy with didanosine may precipitate attacks of gout in
susceptible individuals.
Lamivudine
Lamivudine (3TC) is a nucleoside analog with in vitro activity against HIV-1, including
zidovudine resistant strains, and HBV. Lamivudine inhibits the reverse transcriptase of HIV-1
and is synergistic with zidovudine against HIV-1. As with zidovudine, lamivudine requires
intracellular triphosphorylation for activation. Lamivudine, administered in combination with
zidovudine or another nucleoside analog to retard the emergence of resistance, is indicated for
treatment of advanced HIV disease. Potential side effects are headache, insomnia, fatigue, and
gastrointestinal discomfort, though these are typically mild.
Zalcitabine
Zalcitabine (ddC) is a pyrimidine nucleoside that inhibits the replication of HIV-1. Like
zidovudine, intracellular activation by triphosphorylation is catalyzed by cellular enzymes;
competitive inhibition of the reverse transcriptase and chain termination result. The drug is
effective as treatment for patients with HIV infection. It is available in oral formulation only and is
typically prescribed in combination with zidovudine. Zalcitabine therapy is associated with a
dose-dependent peripheral neuropathy that appears to occur more frequently in patients with
low serum cobalamin levels and in those with a history of excessive ethanol consumption. Other
reported toxicities include pancreatitis, esophageal ulceration and stomatitis, and arthralgias.
Coadministration of drugs that cause either peripheral neuropathy or pancreatitis may increase
the frequency of these adverse effects.
Stavudine
Stavudine (d4T) is a thymidine analog that requires intracellular triphosphorylation for activation,
acting as a competitive inhibitor of HIV-1 reverse transcriptase and as a chain terminator. The
major dose-limiting toxicity is peripheral sensory neuropathy. Less common adverse effects
include pancreatitis, arthralgias, and elevation in serum transaminases.
Protease Inhibitors
Indinavir
Indinavir is a specific inhibitor of the HIV-1 protease, an enzyme essential for the production of
mature, infectious virions. It is currently used for the treatment of individuals with HIV-1 infection
and is recommended for use in combination with a reverse transcriptase inhibitor to delay
emergence of resistance. The drug must be consumed on an empty stomach for maximal
absorption. Oral bioavailability is excellent.
Resistance: Resistance to indinavir is mediated by the expression of multiple and variable
protease amino acid substitutions. At least two-thirds of indinavir-resistant strains are crossresistant to saquinavir and ritonavir; however, saquinavir-resistant isolates tend to retain
susceptibility to indinavir.
Adverse Effects: The most common adverse effects reported thus far are indirect
hyperbilirubinemia and nephrolithiasis. Thrombocytopenia, nausea, diarrhea, and irritability
have also been reported in some patients. Indinavir and ritonavir are inhibitors of as well as
substrates for cytochrome P450 CPY3A4. Serum levels of indinavir will increase in the
presence of antifungal azoles (themselves CYP3A4 inhibitors) and decrease in the presence of
rifabutin and rifampin (CYP3A4 inducers). Increased levels of rifabutin (also a CYP3A4
substrate) that result from use of indinavir require a reduction in the rifabutin dosage by 50%.
Increased levels of antihistamines, cisapride, and benzodiazepines may also occur with
potential toxicity from these drugs. More precise delineation of drug interactions is underway.
Ritonavir
Ritonavir is an inhibitor of HIV-1 protease with a high bioavailability (60-80%). The most
common adverse effects of ritonavir are gastrointestinal disturbances, circumoral paresthesia,
elevated hepatic aminotransferase levels, altered taste, and hypertriglyceridemia. Caution is
advised when administering the drug to persons with impaired hepatic function. This drug
should be refrigerated for storage. HIV-1 isolates resistant to ritonavir are cross-resistant to
indinavir.
Saquinavir
Saquinavir is a synthetic peptide-like substrate analog that inhibits the activity of HIV-1 protease
and prevents the cleavage of viral polyproteins. The in vitro activity of saquinavir against HIV-1
is additive to or synergistic with that of reverse transcriptase inhibitors. As with other agents of
this class, it is likely that combination therapy with nucleoside agents will be optimal clinically.
To date there is little evidence of cross-resistance between saquinavir and other protease
inhibitor compounds or between saquinavir and nucleoside analogs.
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTI)
Nonnucleoside reverse transcriptase inhibitors are a group of structurally diverse antiretroviral
agents that have a similar mechanism of action. Nonnucleoside reverse transcriptase inhibitors
interfere with the function of reverse transcriptase by binding directly to the enzyme in a
noncompetitive fashion. The NNRTIs do not depend on intracellular conversion to an active
metabolite.There are 2 nonnucleoside reverse transcriptase inhibitors commercially available
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Delavirdine (DLV)
Delavirdine a synthetic antiretroviral agent, is a nonnucleoside reverse transcriptase
inhibitor.Delavirdine differs structurally from nevirapine, a dipyridodiazepinone derivative
nonnucleoside reverse transcriptase inhibitor. The drug inhibits replication of HIV-1 by
interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase. The
mechanism of action of DLV derivatives appears to be similar to that of other nonnucleoside
reverse transcriptase inhibitors (e.g., nevirapine, loviride, efavirenz). All nonnucleoside reverse
transcriptase inhibitors appear to bind to a common region of reverse transcriptase and exhibit
similar kinetic characteristics in their mode of retroviral inhibition.
Spectrum: Delavirdine is a highly specific antiretroviral agent with a very limited spectrum of
activity. The drug has in vitro virustatic activity against HIV-1, but is inactive against HIV-2.
Resistance: Strains of HIV-1 with reduced susceptibility to delavirdine (i.e., 10- to 100-fold
decrease in susceptibility from baseline) have been produced in vitro by serial passage of the
retrovirus in the presence of increasing concentrations of the drug. The mechanism of
resistance or reduced susceptibility to delavirdine has not been fully determined, but mutation of
HIV reverse transcriptase appears to be involved.
Clinical Uses: Oral delavirdine is used in combination with other antiretroviral agents for the
management of human immunodeficiency virus type 1 (HIV-1) infection in adults.
Adverse reactions: Rash is the major toxicity associated with delavirdine therapy. Severe or lifethreatening rash (e.g., erythema multiforme, Stevens-Johnson syndrome) have been reported
rarely and resolved after the drug was discontinued. Rash usually is evident within 1-3 weeks
(median: 11 days) following initiation of delavirdine therapy and typically is diffuse,
maculopapular, erythematous, and often pruritic; rash occurs mainly on the upper body and
proximal arms with decreasing intensity of the lesions on the neck and face and progressively
less on the rest of the trunk and limbs.
Nevirapine
Nevirapine is a nonnucleoside reverse transcriptase inhibitor. The drug inhibits replication of
human immunodeficiency virus type 1 (HIV-1) by interfering with viral RNA- and DNA-directed
polymerase activities of reverse transcriptase. Nevirapine binds directly to HIV-1 reverse
transcriptase and exerts a virustatic effect by acting as a specific, noncompetitive HIV-1 reverse
transcriptase inhibitor. Nevirapine is a highly specific antiretroviral agent with a very limited
spectrum of activity.
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Pharmacokinetics: Nevirapine is administered orally. The drug may be taken without regard to
meals. Systemic availability of nevirapine is not affected by concomitant administration with a
substantial meal, an antacid, or with didanosine formulated with an alkaline buffering agent.
Because nevirapine is extensively metabolized by the liver and nevirapine metabolites are
extensively eliminated by the kidneys, the drug should be used with caution in patients with
renal or hepatic dysfunction. The manufacturer states that data currently are insufficient to
recommend a nevirapine dosage for patients who have hepatic dysfunction or renal
insufficiency or are undergoing hemodialysis.
Oral nevirapine is labeled for use in combination with dideoxynucleoside reverse transcriptase
inhibitors for the treatment of HIV-1 infections in adults.
Resistance: Strains of HIV-1 with reduced susceptibility to nevirapine have been produced in
vitro. Strains of HIV-1 resistant to nevirapine may be cross-resistant to some other
nonnucleoside reverse transcriptase inhibitors.
Adverse effects: The drug appears to be well tolerated when administered in combination with
zidovudine (with or without didanosine). The major toxicity associated with nevirapine to date is
rash, including severe or life-threatening rash. Manifestations of severe rash or rash associated
with constitutional symptoms.
Fusion Inhibitors
Enfuvirtide (T-20): Enfuvirtide is the first approved agent in fusion inhibitors. Can be prescribed
in combination with other anteretroviral agents, for experienced HIV patients whose viral load
remains detectable despite ongoing therapy. HIV-1 isolates resistant to NRTIs, NNRTIs ans PIs
were susepteble to enfuvirtide. Enfuvirtide has a robust safety profile.
Other Antiviral Agents
Amantadine, Rimantadine
Amantadine/ rimantadine inhibit uncoating of the viral RNA of influenza A within infected host
cells, thus preventing its replication. Both agents are effective in the prevention of influenza a
virus infection in high-risk individuals. Additionally, both drugs can be used in the treatment of
influenza A, effectively reducing the duration of symptoms when administered within 48 hours
after their onset. The most common side effects are gastrointestinal intolerance and central
nervous system effects (eg, nervousness, difficulty in concentrating, lightheadedness).