Antiviral Therapy: Current Concepts and Practices

37 Pages·2003·7.98 MB·English

CLINICAL MICROBIOLOGY REVIEWS, Apr. 1992, p. 146-182 Vol. 5, No. 2
0893-8512/92/020146-37$02.00/0
Copyright © 1992, American Society for Microbiology
Antiviral Therapy: Current Concepts and Practices
BONNIE BEAN
Departments ofPathology andMedicine, Humana Hospital-MichaelReese, Chicago, Illinois 60616
INTRODUCTION 146
....................................
CELLULAR AND VIRAL REPLICATION.................................... 146
ANTIVIRAL AGENTS 149
....................................
Amantadine and Rimantadine 149
....................................
Ribavirin 153
....................................
Vidarabine 154
....................................
Acyclovir 154
....................................
Ganciclovir 156
....................................
Foscarnet 157
....................................
Zidovudine 158
....................................
Didanosine 159
....................................
Investigational Antiretroviral Agents.................................... 159
IMMUNOGLOBULINS 160
....................................
IMMUNOMODULATORS 162
....................................
PROBLEMS OF ANTWIRAL THERAPY 164
....................................
Resistance.................................... 164
Latency 165
....................................
Immunosuppression byAntiviral Agents.................................... 165
PROSPECTS FOR THE FUTURE 165
....................................
Liposomes 165
....................................
Combination Therapy 166
....................................
Computer-Aided Drug Design 166
....................................
Role ofthe Clinical Microbiology Laboratory.................................... 166
CONCLUSIONS 167
....................................
ACKNOWLEDGMENTS 167
....................................
REFERENCES 167
....................................
INTRODUCTION metabolicallystable. Mostimportant, theymustinhibitvirus
replication without disturbing host cell function. Because
Interest in antiviral chemotherapy began in the 1950s, viruses reproduce intracellularly and use host cell metabolic
when the search for antitumor agents generated a great deal machinery in doing so, it was thought for many years that
of interest in DNA synthesis inhibitors and produced a specific interference with viral replication was impossible.
number of compounds capable of inhibiting viral DNA Experience with early antiviral compounds corroborated
synthesis. Antiviral agents were first successfully adminis- this view; the drugs were either too toxic or insufficiently
teredtopatientsin the 1960s,when Bauerprevented disease potent to be ofuse (460). Two drugs that illustrate this well
by giving thiosemicarbazone (methisazone) to patients ex- are idoxuridine (5-iodo-2'-deoxyuridine) and trifluorothymi-
posed to smallpox (20) and Kaufman greatly improved the
dine (5-trifluoromethyl-2'-deoxyuridine) (Fig. 1). Idoxuri-
healing of herpes keratitis by treating patients with topical
dine was first synthesized by Prusoff in 1959 (363) and was
idoxuridine (233). Progress was slow, however, because of
subsequentlyshown to inhibit a numberofDNAviruses (for
the difficulty in finding compounds capable of inhibiting
a review, see reference 364). When administered systemi-
viruses while at the same time leaving host cell functions
cally to patients, however, it did not decrease the risk of
intact. With the late 1970s and early 1980s came develop-
death from herpes encephalitis and it caused myelosuppres-
ment and marketing of acyclovir, the first antiviral agent
sion in almost all patients who received it (40). On the other
nontoxic enough to be ofvalue in treating a wide range of
herpesvirus infections in ambulatory as well as seriously ill hand, the drug was effective and much less toxic when
patients. The late 1980s and early 1990s are seeing an administered topicallytopatientswithherpeskeratitis(233).
explosion in antiviral agents and in approaches to antiviral It is still used for this purpose. Recently, there has been a
therapy that is fueled, in part, by the AIDS epidemic. This resurgence of interest in topical use of idoxuridine coupled
article reviews the basis of antiviral therapy, the agents withdimethylsulfoxidefortreatmentofherpeslabialis(450).
themselves, theproblemstobesolved, andprospectsforthe Trifluorothymidine, first developed as an antitumor agent,
future. wasfoundtoinhibitherpessimplexvirus(HSV)invitro,but
its selectivity index (ratio of drug concentration causing
cellular toxicity to that needed forviral inhibition) wasvery
CELLULAR ANDVIRAL REPLICATION low compared with those ofother agents (99) and itwas not
Like antibacterial agents, useful antiviral agents must developed for systemic use. Like idoxuridine, it is used for
havecertain properties. Theymustreachtheirtargetorgans, topical treatment of herpes keratitis.
be active intracellularly as well as extracellularly, and be Despite theirshortcomings, these drugswere important in
146
VOL. 5, 1992 ANTIVIRAL THERAPY 147
OH OH
IDOXURIDINE TRIFLUOROTHYMIDINE VIlDARABINE
FIG. 1. Some nucleoside analogs first used as antiviral agents.
that they demonstrated the feasibility ofantiviral therapy in into cDNA which is then inserted into the host cell DNA
patients. They also sustained interest in a continuing search (Fig. 2). Picornaviruses such as rhinoviruses and enterovi-
for more selective agents. By the late 1970s, it was known ruses carry a positive single-stranded RNA that can be
thatmost human pathogenicviruses possess enzymescoded directly translated by host cell enzymes, but they must
bythevirusesthemselves andnotpresent in uninfected cells encode an RNA replicase which allows use of the genomic
(327). Most of these enzymes are involved in viral nucleic RNA as a template for new negative-stranded RNA. Ortho-
acid synthesis, as discussed below. Their discovery repre- myxoviruses (influenza viruses), on the other hand, carry a
sented a major advance in antiviral therapy by making it negative-stranded RNA, and thus must supply an RNA-
possible todirect effortsatfindingspecific inhibitorsofthese dependent RNA polymerase from which a plus-stranded
enzymesratherthan nonspecific inhibitors ofviralgrowth in mRNA can be made. Such unique enzymes, critical toviral
cell culture. replication but unnecessary for cellular function, offer very
Replicationofvirusescanbedividedintoseveral steps: (i) goodtargetsforselective inhibitionbyantiviral agents. They
attachment to the cell, (ii) penetration, (iii) uncoating of are not the only enzyme targets, however.
nucleic acid, (iv) transcription and translation ofearly (reg- Other enzymes such as nucleoside kinases and DNA
ulatory)proteins, (v)nucleic acidsynthesis, (vi) synthesisof polymerases are encoded by both cells and viruses (Fig. 4).
late (structural) proteins, (vii) assembly of mature virions, The properties of such enzymes can differ greatly with
and (viii) release from the cell (for an example, see Fig. 2). respect to substrate specificity, binding affinity for sub-
All of these steps are potential targets for interference, strates, and susceptibility to inhibition by various com-
although viral attachment, penetration, uncoating, assem- pounds. These differences can be exploited in developing
bly, and release closely resemble normal cellular processes antiviral compounds. For example, thymidine kinases cata-
and are thought to be carried out, in many instances, by lyze the first step in the preparation of pyrimidine nucleo-
cellular enzymes (210). It is at the point of nucleic acid sides for incorporation into DNA, phosphorylation ofthe 5'
synthesis that viral processes diverge most from their cellu- carbon atom of the pentose ring (Fig. 4). Thymidine kinase
larcounterpartsandaremostlikelytorequirevirus-specified specified by HSV binds acyclovir much better than cellular
enzymes. This is because eukaryotic cells contain double- thymidine kinase does and phosphorylates it 3 million times
stranded DNA and, when they replicate, make new DNA faster (235). DNA polymerases are responsible for incorpo-
from the parental DNAtemplate in the cell nucleus (Fig. 3). rating nucleotide triphosphates into growing DNA chains,
Inaddition, theytranscribe mRNAfrom DNAandtransport and again, herpesvirus-specified DNA polymerases differ
itintothecytoplasm,whereproteinsaretranslated. Viruses, from their cellular counterparts: they are 30 times more
on the other hand, may contain DNA or RNA as their susceptible to inhibition by acyclovir triphosphate than are
genomic material, and the nucleic acid may be double or the alpha DNA polymerases of human origin (122). Differ-
single stranded, circular or linear, and segmented or in one ences like these make itpossible to identify compounds that
continuous piece. RNA may be either positive or negative selectivelyinhibitviralfunctions. Whatadvantage isthere to
stranded (havingthe same senseordirection asmRNA, and viruses in encoding and carrying enzymes also made by
thus directly translatable, or having the opposite sense and cells? The answer is survival. Viruses carrying the extra
not directly translatable). Viruses may replicate in the nu- enzymes have awiderhost range andcan infectcells that do
cleus, inthecytoplasm, orinboth. Despite thesedifferences not encode a critical enzyme or that express it only at a
fromtheircellular hosts, viruses mustbe able tofit into host certain point in the cell cycle. HSV mutants that do not
cell synthetic pathways ifthey are to replicate successfully. encode thymidine kinase, for example, are less capable of
Theymust present to the cell either a form ofDNAthat can establishingreactivatable latent infections in neurons (which
be transcribed directly into mRNAor a form ofmRNA that are nondividing cells) than are thymidine kinase-encoding
thecellcanrecognizeandtranslateintoproteins(390). Many strains (121, 142, 471).
different pathways have evolved by which viruses accom- Many antiviral agents are nucleoside analogs, structures
plishthis; some examples are shown in Fig. 3. Retroviruses, that closely resemble the natural nucleosides used as build-
for example, carry single-stranded duplex RNA as their ingblocks for DNA synthesis (Fig. 1 and 5). As such, these
genomic material and, when infecting cells, must supply a drugs are phosphorylated by cellular nucleoside kinases and
virus-encoded reverse transcriptase to transcribe this RNA incorporated into growing DNA chains by DNA polymer-
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VOL. 5, 1992 ANTIVIRAL THERAPY 149
RETROVIRUSES
ORTHOMYXOVIRUSES
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FIG. 3. Protein and nucleic acid synthetic pathways foreukaryoticcells(bold) andsome representative humanviruses (dashed lines). *,
need for avirus-specified enzyme; -, negative stranded; +, positive stranded. ss, single stranded; du, duplex; ds, double stranded.
ases, competing with the natural nucleosides as substrates ANTIVIRAL AGENTS
forbothenzymes(Fig.4). Manyoftheearlyantiviral agents,
such as idoxuridine and trifluorothymidine, were equally Amantadine and Rimantadine
good substrates for both viral and cellular kinases. Even
though they were slightly better inhibitors of viral than of The adamantanes, amantadine (1-aminoadamantane hy-
cellular polymerases (194, 365), they were activated and drochloride) and its alpha-methyl derivative, rimantadine,
capable of decreasing DNA synthesis in both infected and are used for management of influenza A virus infections.
They are cyclic amines with bulky, cagelike structures
uninfected cells. Many of the newer nucleosides are less
unlike those ofother known antiviral agents (Fig. 6). Their
toxic, in part because there is at least one point in their
mechanisms of action and spectra of antiviral activity are
functionalpathwayswhichisspecificforvirus-infectedcells.
identical, but rimantadine is metabolized differently from
For example, acyclovir is activated only in virus-infected
amantadine, and itcausesfewercentral nervoussystemside
cells, and zidovudine inhibits an enzyme, human immuno-
effects such as insomnia and difficulty concentrating (110,
deficiency virus (HIV) reverse transcriptase, not found in
514). Itis also a morepotent invitroinhibitorofinfluenzaA
normal cells.
viruses (431), although both drugs have been equally effec-
Although the greatest success has been achieved byusing
tive in treating patients. Amantadine became available in
inhibitors ofnucleic acid synthesis as antiviral agents, addi-
1966; rimantadine is being considered for approval by the
tional enzymes are necessary for other steps in the viral
U.S. Food and DrugAdministration.
replication cycle and should be amenable to inhibition by
It hasbeen known for some time that amantadine inhibits
putative antiviral compounds. Special interest in such com- an early phase ofviral replication (207, 232), more specifi-
pounds has been generated by the AIDS epidemic and the
cally, virus uncoating (48, 381). Recent studies of avian
increasingly obvious need to treat HIV infection with com- influenza viruses have also demonstrated a block at a later
binationsofdrugsactive atdifferentsitesofviralreplication. stage, virus maturation and assembly (184, 461). Suscepti-
Such combination therapy, it is hoped, will decrease drug bility to amantadine is determined principally by the M2
toxicity and reduce the chances of antiviral resistance de- protein(184,281),avirus-specifiedmatrixproteinpresenton
velopingduringtreatment. Unfortunately, stepssuchasviral the surface of infected cells and in the virion in small
attachment and penetration and assembly and release are amounts (530). It has been proposed (28) that this protein
catalyzedbycellular enzymes (210), and it hasbeen difficult forms ion channels through which protons pass across the
to find compounds that interfere specifically with these membranes ofintracellular endocytic and exocyticvesicles.
events. Nevertheless, some success has been achievedwith During virus uncoating, protons are transferred from the
amantadine (an inhibitor of uncoating) for management of endocytic vesicle to the virion, allowing the fall in pH that
influenza, and recombinant soluble CD4 may yet prove releases free viral nucleoprotein into the cell cytoplasm.
effective at inhibiting attachment of HIV to host lympho- During virus assembly, protons are transferred out of the
cytes. Interferons, which inhibit viral mRNA transcription exocyticvesicle, thus maintaining the pH above the level at
and protein synthesis, are also useful as antiviral agents. In which theviral hemagglutinin, amajorsurface glycoprotein,
addition, HIV proteases, which cleave precursor polypep- would lose its structural integrity andfail to be incorporated
tides to form functional reverse transcriptases, are very into the viral envelope. Amantadine appears to block this
promising targets for selective inhibition. M2-mediated transfer of protons and thus inhibits viral
150 BEAN CLIN. MICROBIOL. REV.
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VOL. 5, 1992 ANTIVIRAL THERAPY 151
5H
ACYCLOVIR GUANOSINE RIBAVIRIN
H2N'
N3
OH
GANCICLOVIR ZIDOVUDINE DIDEOXYINOSINE DIDEOXYCYTIDINE
FIG. 5. The purine nucleoside guanosine and some nucleoside analogs currently in use for antiviral therapy.
uncoating or viral maturation or both, depending on the this manner, although lowering the dose ofamantadine also
strain ofvirus (185). At invitro concentrations much higher reduces adverse effects (378, 419). The efficacy oflow-dose
thanthose atwhich these effectsoccur, adamantanes inhibit amantadine has not been proven in this situation, however,
other RNA viruses, including influenza B virus, and and the higher dose remains the prophylactic regimen of
paramyxoviruses (114). With current drug formulations, choice until rimantadine becomes available. Both drugs are
these high concentrations cannot be achieved in patients, more effective in preventing illness than in preventing infec-
and thus the adamantanes remain useful only for the man- tionwithinfluenzaAvirus(110,317).Thismaybebeneficial,
agement ofinfluenza Avirus infections (Table 1). however, in that it allows the patient to produce protective
Both drugs are very effective in preventing illness due to antibodies without developing frank illness. Currently, the
influenza A virus. When given prophylactically during a Immunization Practices Advisory Committee recommends
community outbreak, either compound reduces the risk of using amantadine prophylactically to protect those atriskof
acquiring influenzal illness by50 to 90% ( 68, 110, 161, 317, influenza complicationswho cannotor have notbeenvacci-
331, 500). Rimantadine has fewer side effects when used in nated (60). The drug can also be given at the same time as
NH2 HCI NH2*HCI
H-C-CH3 [
0
-0-p-cl 3 Na
gI 30°
0-
AMANTADINE RIMANTADINE FOSCARNET
FIG. 6. Nonnucleoside antiviral agents.
152 BEAN CLIN. MICROBIOL. REV.
TABLE 1. Antiviral agents currently available and theiruses
Agent Routeofadministration Use Adultdosage
Acyclovir Oral Initialgenital herpes 200mg5timesdailyfor 10days
Recurrentgenital herpes 200mg5 timesdailyfor5 days
Suppression,genital herpes 400mgtwice dailyforupto 1yr
Suppression, mucocutaneous herpes 200mg3 to5 timesdaily
inimmunocompromised host
Treatment, mucocutaneous herpes in 200-400mg5timesdailyuntil healed
immunocompromised host
Zosterin immunocompetent host 800mg5 timesdailyfor7-10 days
Intravenous Herpesencephalitis 10mg/kg3 timesdailyfor 10-21 days
Neonatal herpesa 500mg/mTh 3 timesdailyfor 10days
Severegenital herpes 5 mg/kg3 timesdailyfor5 days
Treatment, mucocutaneous herpes, 5 mg/kg3 timesdailyfor7days
immunocompromised host
Suppression, mucocutaneous herpes 5mg/kg3 timesdaily
in immunocompromised hosta
Zosterorvaricella in immunocom- Adult: 10 mg/kg3timesdailyfor7 days
promised host
Child: 500 mg/mrn 3times dailyfor7days
Topical Initialgenital herpes Applyevery3 hupto 6timesdailyfor7 days
Cutaneous herpesin immunocompro- Applyevery3 hup to 6timesdailyfor7days
mised host
Ganciclovir Intravenous CMVretinitis in AIDS Induction: 5 mg/kgtwice dailyfor 14-21 days
Maintenance: 5 mg/kgdaily
Zidovudine Oral HIVinfection, CD4cells <500/mm3, 100mg5 times daily
orsymptomatic
Vidarabine Intravenous Herpesencephalitis 15 mg/kgdailyover12-24hfor 10days
Neonatal herpes 15 mg/kgdailyover 12-24 hfor10days
Zoster in immunocompromised host 15 mg/kgdailyover 12-24 h for5 days
Ophthalmicointment Herpeskeratitis 0.5 in. [1.27cm] toeye5 times dailyfor7-21
days
Amantadine Oral InfluenzaA: treatment 200mgdailyfor5-7days
InfluenzaA: prophylaxis 200mgdaily
Ribavirin Aerosol Severe RSV, infants andchildren 12-18 h dailyfor3-7 days (concn, 20 mg/ml)
Intravenous Lassafever' 2-gload, then 0.5-1 g3-4timesdailyfor 10
days
Interferon Subcutaneous HepatitisB-chronic active liverdis- 5 x 106 Udaily for4mo
ease'
Hepatitis C-chronic liverdisease 2 x 106-3 x 106 U3 timesweeklyfor6mo
Intralesional Condyloma acuminata (warts) 1 x 106Uperwart in up to5warts 3 times
weekly
Foscarnet Intravenous CMVretinitis Induction: 60mg/kg3 times dailyfor2-3wk
Maintenance: 90-120mg/kgdaily
Acyclovir-resistant HSVorVZVa 40-60mg/kg3 times daily
Didanosine Oral Zidovudine intoleranceortreatment Tablet: 125-300 mg(as2tablets) 2times daily
failure in HIV-infected host
Powder: 167-375 mg2timesdaily
Trifluridine Ophthalmicsolution Herpeskeratitis 1 drop every 2 h up to9 drops dailyuntil
healed
Idoxuridine Ophthalmicsolution Herpeskeratitis 1 drop/h duringdayand every2h at nightun-
til healed
aThepackageinsertisnotapprovedforthisindication.
bSquaremetersofbodysurface area.
VOL. 5, 1992 ANTIVIRAL THERAPY 153
influenza virus vaccine to protect the patient until an anti- the synthesis ofGTP. This inhibition results in a decrease in
body response to the vaccine occurs. the cellular pools of guanine nucleotide necessary for both
Both amantadine and rimantadine have been used for the cellular and viral replication (458, 459). Ribavirin inhibits
treatment of influenza. They are most effective when given capping of viral mRNA (170, 493), a critical step in the
within the first 48 h of illness and may allow the patient to replication of most viruses. Its most important effect, how-
return to routine daily activities 1 to 2 days earlier than no ever, appears to be on the early events ofviral replication.
treatment would (191, 475, 483, 514). Amantadine also Ribavirin directly inhibits viral RNA-dependent RNA poly-
appears superiortoaspirin inthisregard. Inone comparative merase of influenza viruses (129), and it can retard both
study, patients taking 3.25 g ofaspirin daily became afebrile initiation (54, 338, 367, 521) and elongation (129, 521) of
sooner but had more side effects (insomnia, nausea, ringing mRNA transcripts. It is not incorporated into the growing
in the ears) than amantadine recipients, who experienced an chain of viral nucleic acid and does not cause chain termi-
earlier reduction in symptoms and fewer adverse reactions nation (129, 477). Only one strain ofvirus, a mutant offowl
(528). The peripheral pulmonary airway dysfunction accom- plague virus, is known to be resistant to ribavirin (215).
panying influenza is also improved by amantadine (279), and In addition to its antiviral properties, ribavirin has im-
this may be important for earlier resolution in normal hosts munoregulatory effects. In cell culture and in animals, it
and for minimizing disease in those with underlying pulmo- inhibits macromolecular synthesis and cell division (270),
nary or cardiac conditions. The effects of therapy on the lymphocyte proliferation, and nucleic acid synthesis (341). It
complications of influenza, such as pneumonia and myo- also suppresses B lymphocytes and subsequent antibody
carditis, are unknown. production (358) and tumor growth (357). To date, however,
Although drug resistance does not occur naturally among noneofthese effectshasbeen shown tobeofconsequence in
influenza viruses (27), it can be induced by therapy, and patients treated with ribavirin.
these resistant viruses can cause influenzal illness. When The major toxicities of ribavirin are anemia and embryo-
patients ill with influenza were treated with rimantadine, toxicity. Anemia occurs when ribavirin diffuses into eryth-
they improved symptomatically, but 50% of them began rocytes and accumulates, because erythrocytes lack phos-
shedding rimantadine-resistant viruses within 4 to 6 days phatases and are unable to hydrolyze (dephosphorylate) the
(177, 188). In one study, these resistant viruses were appar- drug. The erythrocytes then become damaged as they age
ently transmitted to family members, who also became ill and are removed prematurely from the circulation (52, 334).
with influenza (188). Resistance was mapped to the M2 At very high doses of ribavirin in animals, bone marrow
protein (29), and subsequent studies of similarly resistant suppression of erythroid precursors also occurs (52). All of
avian viruses have shown that these resistant strains are these effects are reversible upon removalofthe drug, butthe
genetically stable and equal invirulence towild-type viruses half-life ofribavirin in human erythrocytes is40 days, so the
(25). These findings raise the possibility that widespread use effect is prolonged. In pregnant rodents treated with ribavi-
of adamantanes for treatment of influenza might result in rin, skeletal defects inthe developingembryo aswell asfetal
antiviral pressure and selection of predominantly resistant resorption have been observed (242). Because of this, the
viruspopulations. Toprevent thespreadofresistantvirus, it drug is contraindicated during pregnancy, and safety mea-
has been suggested that patients be isolated or have limited sures must be taken by pregnant health care workers who
contactwithotherswhile theyarebeing treatedfor influenza administer ribavirin to patients (see below).
(186). The effects of this and other methods to control Ribavirin became commercially available for use as an
transmission are unknown, however. In view ofthese prob- aerosol in 1986. Both the oral and intravenous forms have
lems and of the unknown effect of therapy in preventing or been studied, but the drug was found to be most effective
relieving complications, no recommendation for therapy of when given to animals by pulmonary aerosol, so it was
influenza is currently made by the Centers for Disease developed for that purpose. The drug is diluted in a reser-
Control (60), although amantadine is approved for this voir, nebulized by a small-particle aerosol generator, and
purpose (package insert). delivered to the patient via face mask, ventilator, or infant
oxygen hood. Aerosolized drug can leak from the system
during administration and may be inhaled by health care
Ribavirin
workers. This may represent a hazard to pregnant workers,
Ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carbox- although it is not known whether the small amounts ab-
amide) was first synthesized in the early 1970s as part ofan sorbed into the bloodstream will damage the fetus (57).
intensive effortto identify newantiviral agents (517). At first In college students with uncomplicated influenza, aerosol
glance, it appears to be a nucleoside analog with an open ribavirin reduced the duration of fever and symptoms and
pyrimidine ring (Fig. 5). Structurally (362) and functionally decreased viral shedding (239, 291, 513). This has not been
(458), however, it most closely resembles guanosine. Riba- true of all trials and for all influenza variants, however (33,
virin is active in vitro against a wide variety of RNA and 167). Because of this inconsistency and because aerosol
DNA viruses, including adenoviruses, herpesviruses, influ- therapy is an expensive and cumbersome mode of therapy
enza A and B viruses (429, 517), respiratory syncytial virus for a self-limited illness, ribavirin is not often used in this
(RSV) (212), bunyaviruses, arenaviruses (214), reoviruses setting.
(367), and HIV (292). In infants with bronchiolitis due to RSV, ribavirin has
The mode of action has not been clearly defined. Three shown some effect in decreasing viral shedding, improving
mechanisms have been proposed, and all may operate to oxygenation, and reducing the duration ofillness (178, 179,
some extent in cells infected by different viruses. This may 388, 469), although questions have been raised about the
also account for the wide spectrum of activity. Ribavirin methods used in treatment trials (494). In a recent trial,
readily diffuses into eukaryotic cells, where it is converted ribavirindecreasedthedurationofoxygentherapy, mechan-
by cellular enzymes to the mono-, di-, and triphosphate ical ventilation, and hospital stay in otherwise healthy in-
forms (437, 458). The monophosphate is a potent competi- fantswith severe RSVillness (439). Nevertheless, important
tiveinhibitorofIMPdehydrogenase, anenzymeessentialfor questionsremainunanswered, includingdurationoftherapy,
154 BEAN CLIN. MICROBIOL. REV.
response ofchildren with underlyingcardiacand pulmonary eated, but it involves phosphorylation of the nucleoside by
disease, and efficacy of the drug when administered late in cellular enzymes (44, 355) and incorporation into the grow-
the course of illness (368). Ribavirin is extremely expensive ing chains of both cellular and viral DNAs, with resultant
($400 per day in drug costs alone), and all children with slowing ofDNA synthesis (343). Vidarabine triphosphate is
self-limited RSV cannot be hospitalized and treated. Along also a competitive inhibitor of DNA polymerase, both cel-
with the possible toxicity for health care workers, these lular and viral. It is more potent, however, against viral
unanswered questions indicate the great need for additional enzymes, and this potency may account for its selective
studiesto define theoptimumuse ofthis drugfor respiratory inhibition ofviral DNA synthesis (117, 417).
viral disease. Vidarabine inhibits other steps in nucleic acid synthesis,
Because of its in vitro activity against bunyaviruses and such as RNA polyadenylation (393) and terminal deoxynu-
arenaviruses, intravenous ribavirin hasbeeninvestigatedfor cleotidyl transferase (108), butwhetherornotthesecontrib-
treatment of viral hemorrhagic fevers (214). Most notable ute to its antiviral activity is unknown. It also inhibits
hasbeen the successwith Lassafever. Whenpatientsathigh S-adenosylhomocysteine hydrolase (398), an enzyme neces-
risk of death from Lassa fever were treated intravenously sary for methylation of tRNA and mRNA and for other
within 6 days of fever onset, the death rate of55 to 76% in cellulartransmethylationreactions.Thisinhibitionresults in
placebo-treated patients decreased to 5 to 9% in ribavirin cytotoxicity for mononuclear cells and in the possible accu-
recipients (293). Oral ribavirin is also beneficial against mulation of biogenic amines (117), both of which may
Lassa feverand is given as prophylaxisto high-risk contacts contribute to the toxicity of this compound.
ofLassa fever patients (58). Recent small-scale studies have Vidarabine became available as an eye ointment in 1977
shown that ribavirin crosses the blood-brain barrier well, and remains useful for the treatment of herpes keratitis
giving drug levels in the cerebrospinal fluid that are 50 to (Table 1). Although itis alsouseful forthetreatmentofHSV
100% ofthose in serum (82, 330). Forthisreason, itmayalso and VZV in immunocompromised patients (502, 504, 507,
be of use in the treatment of common viral encephalitides 510) and for herpes encephalitis (508, 509) and neonatal
caused bybunyaviruses, such as La Crosse encephalitis (54, herpes (506, 511), it has been almost entirely replaced by
214). acyclovir for these diseases. Vidarabine is difficult to use. It
Ribavirinhas recentlybeen investigatedforpossibleuse in is poorly soluble in water and rapidly deaminated invivo to
HIV-infectedpatients. Althoughthe druggivenorallyinhigh arahypoxanthine, a much less active compound. It must
doses appeared to delay progression to AIDS (384), many therefore be administered continuously by the intravenous
questions have been raised about the study methodology route in large volumes offluid. Toxicities, including nausea
(39). In addition, no effects on surrogate markers of HIV and vomiting, weakness, weight loss, megaloblastosis of
progression (CD4 counts, p24 antigenemia, viremia, or im- bone marrow erythroid precursors, tremors, and myoclonus
mune function) were found, and it is not clear that clinically have been seen in a high proportion oftreated patients (287,
achievable drug levels are inhibitory for viral replication 394). Acyclovir is easier to administer, less toxic, and more
(292, 385-387). In view of these problems, licensure of active against herpesviruses. Although vidarabine does not
ribavirin for treatment ofHIV is no longer being pursued in require a virus-coded thymidine kinase for activation, and
the United States, although the drug is available in other thymidine kinase-deficient HSV isolates are susceptible to
countries. the drug in vitro, vidarabine has not proven useful for
The place of ribavirin in our armamentarium of antiviral treatment of acyclovir-resistant HSV in HIV-infected pa-
agents is not yet clear. Though useful in aerosol form, it is tients, and foscarnet is preferred (402).
cumbersome, expensive, and perhaps toxic. Intravenous
ribavirin is very useful for life-threatening illness, such as Acyclovir
Lassa fever, but toxicity limits the use of this form in less
severe diseases. Liposome-encapsulated ribavirin has been Acyclovir [9-(2-hydroxyethoxymethyl)guanine] has the
used successfully in animal models for treatment of Rift best therapeutic index ofavailable antiviral agents, and it is
Valleyfever and influenza (163, 236), and it may represent a widely used for the treatment of herpesvirus infections. It
way to achieve improved drug delivery to target organs was "discovered" in the mid-1970sby Elion and colleagues
while minimizing toxicity. Analogs of ribavirin have whiletheywere screeningforantiviralactivityofnucleoside
been synthesized and tested for antiviral activity. One com- analogs (410). Thecompound is an analogofguanosine (Fig.
pound, 5-ethynyl-1-beta-ribofuranosylimidazole-4-carboxa- 5), but instead of a complete ribose ring attached to the
mide (EICAR), was originally studied as an antileukemic purine base, it has an acyclic side chain. Acyclovir diffuses
agentbut has nowbeen shown to be 10 to 30 times as active freelyintocellsbutisactivatedandaccumulatesonlyincells
asribavirin against RSV and influenzaviruses (98). Whether infected with herpesviruses because the first step in activa-
it will be clinically useful remains to be seen. tion, phosphorylation at the 5' position ofthe side chain, is
catalyzedonlyby avirus-specified thymidine kinase and not
to any appreciable extent by cellular kinases (Fig. 4) (122,
Vidarabine
159). Further phosphorylations to the diphosphate and the
Vidarabine (9-beta-D-arabinofuranosyladenine) was the active triphosphate forms are carried out by cellular en-
firstantiviralagentlicensedforintravenoususeintheUnited zymes (122, 312). During DNA replication, acyclovir
States, in 1978. It is an analog of the nucleoside adenosine triphosphate competeswith the natural substrate, dGTP, for
(Fig. 1) and was originally synthesized and studied in the the viral DNA polymerase. It has a higher affinity for the
early 1960s as an antitumor agent. Subsequently, it was enzyme, however, and ispreferentiallyincorporatedintothe
found to be active in vitro against HSV, varicella-zoster growing chain of viral DNA (122, 453). Because the 3'
virus (VZV), cytomegalovirus (CMV), vaccinia virus, and hydroxyl is missing from the attached acyclovir molecule,
some RNA tumor viruses. In animal models, it was active thenextnucleotidecannotbeattached, andDNAreplication
against HSV and vacciniavirus (409). isterminated(103, 156, 294).Furthermore,whenacycloviris
The mechanism of action has not been completely delin- bound to the DNA template in the presence of the next
VOL. 5, 1992 ANTIVIRAL THERAPY 155
nucleotide, a tight irreversible complex is formed and the (282, 373). Topical therapy is occasionally used in pregnant
polymerase is completely inactivated, further slowing viral patientswho have mild genital herpes and should not receive
DNA synthesis (103, 158, 369). Taken together, these prop- systemic acyclovir.
erties make acyclovir highly selective in inhibiting viral Oral treatment of herpes labialis (the common cold sore)
replication while having little effect on host cell function. shortens the course ofillness in those patientswho are prone
There is, for instance, a 3,000-fold difference between the to more severe eruptions and are able to initiate therapy
concentration of acyclovir needed to inhibit HSV type 1 themselves at the first sign ofan eruption (451). When given
(HSV-1) and that needed to inhibit the cells in which it is prophylactically to patients exposed to the sun orto artificial
grown (122). UV light, oral acyclovir decreased the frequency ofherpetic
The herpesviruses vary in their susceptibilities to acyclo- lesions appearing within the next 2 or 7 days, respectively
vir. HSV-1 and HSV-2 are exquisitely susceptible, requiring (448, 449) but did not affect the lesions which appeared
mean in vitro concentrations of 0.04 and 0.4 ,ug/ml, respec- immediately (within 48 h) after the exposure (448). Topical
tively, for 50% inhibition of viral replication (86, 329). The therapy is of little benefit in otherwise healthy patients with
thymidine kinase ofVZV does not phosphorylate acyclovir cold sores (448, 520). In the treatment ofherpes encephalitis,
as effectively, and the virus is 8 to 10 times less susceptible acyclovir has proven both more effective and less toxic than
to the drug than HSV (35, 86, 329). Although its DNA vidarabine (434, 503). It reduces morbidity to 14% (vidara-
polymerase isverysusceptible toacyclovir(452), CMVdoes bine reduces it to38%), and it is now the treatment ofchoice
not encode a thymidine kinase (133), and high drug levels (5 for that disease. Arecent trial ofacyclovirversusvidarabine
to 25 ,ug/ml) are required for inhibition (86, 353). It is not for the treatment of neonatal herpes showed neither drug to
clear that Epstein-Barr virus (EBV) encodes a thymidine be superior (501). Given the sample size, however, as much
kinase capable of activating acyclovir. Its DNA polymerase as a 25% difference in morbidity and mortality could have
is, however, very susceptible to the drug (91), and the 50% been present and gone undetected.
inhibitoryconcentrations are low (73, 278). Acyclovir has no Acyclovir has also been very useful for management of
effect on the latent phase of any of the herpesviruses. mucocutaneous HSV in immunocompromised patients. Ad-
Acyclovir is available in three formulations: an ointment, ministered orally or intravenously, it decreases pain and
pills or capsules, and an intravenous suspension. Systemic viral sheddingand accelerates healing (310, 425). Though not
absorption and other side effects of the ointment are mini- as effective, topical therapy can also be useful in this regard
mal, but it is not very effective (see below) and has largely (505). When given suppressively to HSV-seropositive pa-
been replaced by oral formulations. Levels achieved in tients, acyclovir greatly reduces the chances ofa recurrence
serum after intravenous administration are well above the during subsequent chemotherapy (405) or transplantation
inhibitory concentrations of HSV, VZV, EBV, and some (406, 418, 423, 492).
strains ofCMV. With oral dosing, however, only 15 to 20% VZV infection responds better to intravenous than to oral
of the medication is absorbed, and levels in serum are not acyclovir, probably because levels in serum after oral ad-
consistently above the inhibitory concentrations for any of ministration are often below the 50% inhibitory dose for the
the herpesviruses except HSV (100). virus. In immunocompromised patients with chickenpox or
Acyclovir is remarkably free of serious toxicity. When zoster, intravenous acyclovir has been very effective in
given intravenously in high doses, it can cause a transient decreasing dissemination and other complications (15, 326,
rise in serum creatinine that is apparently due to obstructed 361, 424). Itcanalsobegivenorallyinthepost-bone marrow
renal tubules (22, 407). A reversible neurologic syndrome transplantation period and appears to decrease the fre-
consisting of confusion, lethargy, and occasionally halluci- quency of zoster during that time (346, 421). In otherwise
nations and coma has alsobeen described. This syndrome is healthy patients with zoster, intravenous acyclovir de-
usually seen in very ill, immunocompromised patients re- creases acute pain and accelerates lesion healing (23, 350),
ceiving high-dose intravenous therapy (137, 253, 491). With but oral therapy has had only a modest effect against this
oral therapy, nausea, diarrhea, and headache have occasion- disease (213, 296). Neitherform oftherapy reducesposther-
ally been reported. Acyclovir is not carcinogenic and is petic neuralgia. Ofimportance, oral acyclovir decreases the
mitogenic or teratogenic only at very high levels in animals frequency of eye complications in patients with ophthalmic
(479). It does cross the placenta, however, and therefore zoster (69, 70). In one study of otherwise healthy children
must be used with caution in pregnant patients (45, 172). with chickenpox, oral acyclovir reduced the duration of
Acyclovir is very effective for the treatment of HSV in disease by 1 daybut did not influence the complication rate,
otherwise healthy patients (Table 1). When given orally or days offfrom school, or transmission rate within the family
intravenously, it shortens the course ofinitial genital herpes (18). In otherwise healthy adults with chickenpox pneumo-
by one-third to one-half(46, 79, 314, 323). Recurrentgenital nia, intravenous acyclovir appears to hasten recovery (175).
herpesdoesnotrespondasdramatically, evenwhenpatients Despite the reduced susceptibility of CMV to acyclovir,
initiate therapy themselves at the first sign of disease (323, the drug may yet prove useful in the management of CMV
374). This may be because recurrences normally last only a disease in immunocompromised patients. Two studies, one
few days, andit isdifficulttodemonstrate ashorteningofthe of bone marrow recipients (309) and one of renal allograft
coursewithdrugtherapy.Acycloviris, however,veryuseful recipients (17), have suggested that high-dose intravenous
in preventing recurrent disease. When given daily in low acyclovir can reduce the frequency of CMV infection and
dosestopatientswith frequenteruptions, it suppressesthem disease when given suppressively in the peritransplantation
almost completely and causes no side effects even with period. The reasons for this are not clear, but may relate to
prolonged use (112, 230, 306, 313). It does not prevent the fact that only low numbers ofviruses are present early
asymptomatic viral shedding (457), and transmission has after reactivation, and the small amount ofactive acyclovir
occurred when patients were free of genital lesions (392). present maybe sufficient to limitviral replication enough to
Topical acyclovir, a 5% ointment, is useful, though not as prevent clinical disease. Acyclovir therapy of established
effective as oral therapy, for treatment of initial genital CMV infections in immunocompromised patients has not
herpes (79, 80, 472). In recurrent disease it offers no benefit been successful (16, 489).