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Antiviral Drugs
I. OVERVIEW
Viruses are obligate intracellular parasites. They lack both a cell wall and a cell
membrane, and they do not carry out metabolic processes. Viral reproduction uses much
of the host’s metabolic machinery, and few drugs are selective enough to prevent viral
replication without injury to the host.
II. TREATMENT OF RESPIRATORY VIRUS INFECTIONS
Viral respiratory tract infections for which treatments exist include those of influenza A
and B and respiratory syncytial virus (RSV).
A.
Neuraminidase inhibitors
Orthomyxoviruses that cause influenza contain the enzyme neura- minidase, which is
essential to the life cycle of the virus. Viral neura- minidase can be selectively inhibited
by the sialic acid analogs, oseltamivir and zanamivir. Oseltamivir and zanamivir are
effective against both Type A and Type B influenza viruses. They do not interfere with
the immune response to influenza A vaccine. Administered prior to exposure, neura-
inidase inhibitors m prevent infection, and, when administered within the first 24 to 48
hours after the onset of infection, they have a modest effect on the intensity and duration
of symptoms.
1. Mode of action: Oseltamivir and zanamivir are transition-state analogs of the sialic
acid substrate and serve as inhibitors of the enzyme activity.
2. Pharmacokinetics: Oseltamivir is an orally active prodrug that is rapidly hydrolyzed by
the liver to its active form. Zanamivir, on the other hand, is not active orally and is either
inhaled or administered intranasally. Both drugs are eliminated unchanged in the urine.
3. Adverse effects: The most common side effects of oseltamivir are gastrointestinal (GI)
discomfort and nausea. Zanamivir should be avoided in individuals with severe reactive
asthma or chronic obstructive respiratory disease, because bronchospasm may occur with
the risk of fatality.
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4. Resistance: Mutations of the neuraminidase enzyme have been identified in adults
treated with either of the neuraminidase inhibitors. These mutants, however, are often
less infective and virulent than the wild type.
B. Inhibitors of viral uncoating
Amantadine and rimantadine, is limited to influenza A infections, for which the drugs
have been shown to be equally effective in both treatment and prevention. For example,
these drugs are 70 to 90 percent effective in preventing infection if treatment is begun at
the time of, or prior to, exposure to the virus. Also, both drugs reduce the duration and
severity of systemic symptoms if started within the first 48 hours after exposure to the
virus.
1. Mode of action: The primary antiviral mechanism of amantadine and rimantadine is to
block the viral membrane matrix protein, M2, which functions as a channel for hydrogen
ions. This channel is required for the fusion of the viral membrane with the cell
membrane that ultimately forms the endosome (created when the virus is internalized by
endocytosis).
2. Pharmacokinetics: Both drugs are well absorbed orally. Amantadine distributes
throughout the body and readily penetrates into the central nervous system (CNS),
whereas rimantadine does not cross the blood-brain barrier. Rimantadine is extensively
metabolized by the liver, and eliminated by the kidney.
3. Adverse effects: Minor neurologic symptoms include insomnia, dizziness, and ataxia.
More serious side effects have been reported (for example, hallucinations and seizures).
The drug should be employed cautiously in patients with psychiatric problems.
Rimantadine causes fewer CNS reactions, because it does not efficiently cross the blood-
brain barrier.
4. Resistance: Resistance can develop rapidly in up to 50 percent of treated individuals.
Resistance has been shown to result from a change in one amino acid of the M2 matrix
protein.
C. Ribavirin
Ribavirin is a synthetic guanosine analog. Ribavirin is used in treating infants and young
children with severe RSV infections. [Note: It is not indicated for use in adults with
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RSV.] Ribavirin is also effective in chronic hepatitis C infections when used in
combination with interferon-α. Ribavirin may reduce the mortality and viremia of Lassa
fever.
1. Mode of action: Ribavirin-triphosphate, which exerts its antiviral action by inhibiting
guanosine triphosphate formation, preventing viral messenger RNA (mRNA) capping,
and blocking RNA-dependent RNA polymerase.
2. Pharmacokinetics: Ribavirin is effective orally and intravenously. Absorption is
increased if the drug is taken with a fatty meal. An aerosol is used in certain respiratory
viral conditions such as the treatment of RSV infection.
3. Adverse effects: Side effects reported for oral or parenteral use of ribavirin have
included dose-dependent transient anemia. Elevated bilirubin has been reported. The
aerosol may be safer, although respiratory function in infants can deteriorate quickly after
initiation of aerosol treatment.
III. TREATMENT OF HEPATIC VIRAL INFECTIONS
The hepatitis viruses thus far identified (A, B, C, D, and E) each have a pathogenesis
specifically involving replication in and destruction of hepatocytes. Of this group,
hepatitis B and hepatitis C are the most common causes of chronic hepatitis, cirrhosis,
and hepatocellular carcinoma. Chronic hepatitis B may be treated with peginterferonα-2a,
which is injected subcutaneously once weekly. [Note: Interferon-α2b injected
intramuscularly or subcutaneously three times weekly is also useful in the treatment of
hepatitis B, but peginteferon-α-2a has similar or slightly better efficacy.] Oral therapy
includes lamivudine, adefovir, entecavir, tenofovir, or telbivudine. In the treatment of
chronic hepatitis C, the preferred treatment is the combination of peginterferon-α-2a or
peginterferon-α-2b plus ribavirin.
A.
Interferon
Interferon is a family of naturally occurring, inducible glycoproteins that interfere with
the ability of viruses to infect cells. The interferons are synthesized by recombinant DNA
technology. At least three types of interferons exist, α, β, and γ. One of the 15 interferon-
α glycoproteins, interferon-α-2b, has been approved for treatment of hepatitis B and C,
condylomata acuminata, and cancers such as hairycell leukemia and Kaposi sarcoma.
Interferon-β has some effectiveness in the treatment of multiple sclerosis. In so-called
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“pegylated” formulations. The larger molecular size delays absorption from the injection
site, lengthens the duration of action of the drug, and also decreases its clearance.
1.
Mode of action: It appears to involve the induction of host cell enzymes that
inhibit viral RNA translation, ultimately leading to the degradation of viral mRNA and
tRNA.
2.
Pharmacokinetics: Interferon is not active orally, but it may be administered
intralesionally, subcutaneously, or intravenously. Very little active compound is found in
the plasma, and its presence is not correlated with clinical responses. Cellular uptake and
metabolism by the liver and kidney account for the disappearance of interferon from the
plasma. Negligible renal elimination occurs.
3.
Adverse effects: Adverse effects include flu-like symptoms on injection, such as
fever, chills, myalgias, arthralgias, and GI disturbances. Fatigue and mental depression
are common. These symptoms subside with subsequent administrations. The principal
dose-limiting toxicities are bone marrow suppression including granulo- ytopenia; c
neurotoxicity characterized by somnolence and behavioral disturbances; severe fatigue
and weight loss; autoimmune disorders such as thyroiditis; and, rarely, cardiovascular
problems such as congestive heart failure. Acute hypersensitivity reactions and hepatic
failure are rare.
4.
Drug interactions: Interferon interferes with hepatic drug metabolism, and toxic
accumulations of theophylline have been reported. Interferon may also potentiate the
myelosuppression caused by other bone marrow–depressing agents such as zidovudine.
B.
Lamivudine
This cytosine analog is an inhibitor of both hepatitis B virus (HBV) DNA polymerase and
human immunodeficiency virus (HIV) reverse transcriptase. Lamivudine must be
phosphorylated by host cellular enzymes to the triphosphate (active) form. This
compound competitively inhibits HBV DNA polymerase at concentrations that have
negligible effects on host DNA polymerase. Lamivudine is well absorbed orally and is
widely distributed. Its plasma half-life is about 9 hours. Seventy percent is excreted
unchanged in urine.
C.
Adefovir
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Adefovir dipivoxil is a nucleotide analog that is phosphorylated to adefovir diphosphate ,
which is then incorporated into viral DNA. This leads to termination of further DNA
synthesis and prevents viral replication. Adefovir is administered once a day and is
excreted in urine, with 45 percent as the active compound. Clearance is influenced by
renal function. Both decreased viral load and improved liver function have occurred in
patients treated with adefovir. As with other agents, discontinuation of adefovir results in
severe exacerbation of hepatitis in about 25 percent of patients. The drug should be used
cautiously in patients with existing renal dysfunction.
D.
Entecavir
Entecavir is a guanosine analog approved for the treatment of HBV infections. Following
intracellular phosphorylation to the triphosphate, it competes with the natural substrate,
deoxyguanosine triphosphate, for viral reverse transcriptase. Entecavir has been shown to
be effective against lamivudine-resistant strains of HBV. Liver inflammation and scarring
are improved. Entecavir need only be given once a day.
E.
Telbivudine
Telbivudine is a thymidine analog that can be used in the treatment of HBV. Unlike
lamivudine and adefovir, telbivudine is not active against HIV or other viruses. The drug
is phosphorylated intracellularly to the triphosphate. The drug is administered orally,
once a day, with or without food. Telbivudine is eliminated by glomerular filtration as the
unchanged drug, and no metabolites have been detected. The dose must be adjusted in
renal failure.
F. Tenofovir
IV. TREATMENT OF HERPESVIRUS INFECTIONS
A. Acyclovir
Acyclovir (acycloguanosine) is the prototypic antiherpetic therapeutic agent. It has a
greater specificity than vidarabine against herpesviruses. Herpes simplex virus (HSV)
Types 1 and 2, varicella-zoster virus (VZV), and some Epstein-Barr virus–mediated
infections are sensitive to acyclovir. It is the treatment of choice in HSV encephalitis. The
most common use of acyclovir is in therapy for genital herpes infections. It is also given
prophylactically before bone marrow and after heart transplants.
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1. Mode of action: Acyclovir triphosphate competes with deoxyguanosine triphosphate as
a substrate for viral DNA polymerase and is itself incorporated into the viral DNA,
causing premature DNA-chain termination. The drug is less effective against the host
enzyme.
2. Pharmacokinetics: Administration of acyclovir can be by an intravenous (IV), oral, or
topical route. The drug distributes well throughout the body, including the cerebrospinal
fluid (CSF). Acyclovir is partially metabolized to an inactive product. Excretion into the
urine occurs both by glomerular filtration and by tubular secretion. Acyclovir
accumulates in patients with renal failure.
3. Adverse effects: Side effects of acyclovir treatment depend on the route of
administration. For example, local irritation may occur from topical application;
headache, diarrhea, nausea, and vomiting may result after oral administration. Transient
renal dysfunction may occur at high doses or in a dehydrated patient receiving the drug
IV. High-dose valacyclovir can cause GI problems and thrombotic thrombocytopenic
purpura in patients with AIDS.
4. Resistance: Altered or deficient thymidine kinase and DNA polymerases have been
found in some resistant viral strains and are most commonly isolated from
immunocompromised patients.
B. Cidofovir
Cidofovir is approved for treatment of CMV-induced retinitis in patients with AIDS.
Cidofovir is a nucleotide analog of cytosine, the phosphorylation of which is not
dependent on viral enzymes. It inhibits viral DNA synthesis. Cidofovir is available for
IV, intravitreal (injection into the eye’s vitreous humor between the lens and the retina),
and topical administration. Cidofovir produces significant toxicity to the kidney, and it is
contraindicated in patients with preexisting renal impairment. Neutropenia, metabolic
acidosis, and ocular hypotony also occur. Probenecid must be co-administered with
cidofovir to reduce the risk of nephrotoxicity. Since the introduction of HAART (highly
active antiretroviral therapy), the prevalence of CMV infections in immunocompromised
hosts has markedly declined, and the importance of cidofovir in the treatment of these
patients has also diminished.
C. Fomivirsen
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Fomivirsen is oligonucleotide directed against CMV mRNA. Its use is limited to those
who cannot tolerate or have failed other therapies for CMV retinitis. The drug is
administered intravitreally. The common adverse effects include iritis, vitritis, and
changes in vision.
D. Foscarnet
E. Ganciclovir
Ganciclovir is an analog of acyclovir that has 8 to 20 times greater activity against CMV,
which is the only viral infection for which it is approved. It is currently available for
treatment of CMV retinitis in immunocompromised patients and for CMV prophylaxis in
transplant patients.
1. Mode of action: Like acyclovir, ganciclovir is activated through conversion to the
nucleoside triphosphate. The nucleotide competitively inhibits viral DNA polymerase and
can be incorporated into the DNA, thereby decreasing the rate of chain elongation.
2. Pharmacokinetics: Ganciclovir is administered IV and distributes throughout the body,
including the CSF. Excretion into the urine occurs through glomerular filtration and
tubular secretion. Valganciclovir, like valacyclovir, valganciclovir has high oral
bioavailability, because rapid hydrolysis in the intestine and liver after oral administration
leads to high levels of ganciclovir.
3. Adverse effects: Adverse effects include severe, dose-dependent neutropenia.
Ganciclovir is carcinogenic as well as embryotoxic and teratogenic in experimental
animals.
4. Resistance: Resistant CMV strains have been detected that have lower levels of
ganciclovir triphosphate .
F. Penciclovir and famciclovir
Penciclovir is active against HSV-1, HSV-2, and VZV. Penciclovir is only administered
topically. It is monophosphorylated by viral thymidine kinase, and cellular enzymes form
the nucleoside triphosphate, which inhibits HSV DNA polymerase. Penciclovir
triphosphate has an intracellular half-life 20 to 30-fold longer than does acyclovir
triphosphate. Famciclovir, is a prodrug that is metabolized to the active penciclovir. The
antiviral spectrum is similar to that of ganciclovir, but it is presently approved only for
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treatment of acute herpes zoster. The drug is effective orally. Adverse effects include
headaches and nausea. Studies in experimental animals have shown an increased
incidence of mammary adenocarcinomas and testicular toxicity.
G.
Vidarabine (ara-A)
Vidarabine is active against HSV
‐1, HSV-2, and VZV, its use is limited to treatment of
immunocompromised patients with herpetic and vaccinial keratitis and in HSV
keratoconjunctivitis. [Note: Vidarabine is only available as an ophthalmic ointment.]
Vidarabine, an adenosine analog, is converted in the cell to its 5’-triphosphate analog,
which is postulated to inhibit viral DNA synthesis. Some resistant HSV mutants have
been detected that have altered polymerase.
H.
Trifluridine
Trifluridine is a fluorinated pyrimidine nucleoside analog. It is structurally very similar to
thymidine. Trifluridine is active against HSV-1, HSV-2, and vaccinia virus. It is
generally considered to be the drug of choice for treatment of HSV keratoconjunctivitis
and recurrent epithelial keratitis. Because the triphosphate form of trifluridine can also
incorporate to some degree into cellular DNA, the drug is considered to be too toxic for
systemic use. Therefore, the use of trifluridine is restricted to topical application as a
solution to the eye. A short half-life of approximately 12 minutes necessitates that the
drug be applied frequently. Side effects include a transient irritation of the eye and
palpebral (eyelid) edema.
V. OVERVIEW OF THE TREATMENT FOR HIV INFECTION
Prior to approval of zidovudine in 1987, treatment of HIV infections focused on
decreasing the occurrence of opportunistic infections that caused a high degree of
morbidity and mortality in AIDS patients rather than on inhibiting HIV itself. Today, the
viral life cycle is understood, and a highly active regimen is employed that uses
combinations of drugs to suppress replication of HIV and restore the number of CD4+
cells and immunocompetence to the host. This multidrug regimen is commonly referred
to as “highly active antiretroviral therapy,” or HAART. There are five classes of
antiretroviral drugs, each of which targets one of four viral processes. These classes of
drugs are nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs),
nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, entry
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inhibitors, and the integrase inhibitors. The current recommendation for primary therapy
is to administer two NRTIs with either a protease inhibitor, an NNRTI, or an integrase
inhibitor. Selection of the appropriate combination is based on 1) avoiding the use of two
agents of the same nucleoside analog; 2) avoiding overlapping toxicities and genotypic
and phenotypic characteristics of the virus; 3) patient factors, such as disease symptoms
and concurrent illnesses; 4) impact of drug interactions; and 5) ease of adherence to a
frequently complex administration regimen. The goals of therapy are to maximally and
durably suppress viral load replication, to restore and preserve immunologic function, to
reduce HIV-related morbidity and mortality, and to improve quality of life.