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CLINICAL MICROBIOLOGY REVIEWS, Apr. 1992, p. 146-182 Vol. 5, No. 20893-8512/92/020146-37$02.00/0Copyright © 1992, American Society for Microbiology

Antiviral Therapy: Current Concepts and PracticesBONNIE BEAN

Departments of Pathology and Medicine, Humana Hospital-Michael Reese, Chicago, Illinois 60616

INTRODUCTION .................................... 146CELLULAR AND VIRAL REPLICATION .................................... 146ANTIVIRAL AGENTS.................................... 149Amantadine and Rimantadine.................................... 149Ribavirin.................................... 153Vidarabine.................................... 154Acyclovir.................................... 154Ganciclovir.................................... 156Foscarnet .................................... 157Zidovudine .................................... 158Didanosine.................................... 159Investigational Antiretroviral Agents .................................... 159

IMMUNOGLOBULINS.................................... 160IMMUNOMODULATORS.................................... 162PROBLEMS OF ANTWIRAL THERAPY .................................... 164

Resistance.................................... 164Latency.................................... 165Immunosuppression by Antiviral Agents .................................... 165

PROSPECTS FOR THE FUTURE .................................... 165Liposomes .................................... 165Combination Therapy .................................... 166Computer-Aided Drug Design.................................... 166Role of the Clinical Microbiology Laboratory.................................... 166

CONCLUSIONS.................................... 167ACKNOWLEDGMENTS.................................... 167REFERENCES.................................... 167

INTRODUCTION

Interest in antiviral chemotherapy began in the 1950s,when the search for antitumor agents generated a great dealof interest in DNA synthesis inhibitors and produced anumber of compounds capable of inhibiting viral DNAsynthesis. Antiviral agents were first successfully adminis-tered to patients in the 1960s, when Bauer prevented diseaseby giving thiosemicarbazone (methisazone) to patients ex-posed to smallpox (20) and Kaufman greatly improved thehealing of herpes keratitis by treating patients with topicalidoxuridine (233). Progress was slow, however, because ofthe difficulty in finding compounds capable of inhibitingviruses while at the same time leaving host cell functionsintact. With the late 1970s and early 1980s came develop-ment and marketing of acyclovir, the first antiviral agentnontoxic enough to be of value in treating a wide range ofherpesvirus infections in ambulatory as well as seriously illpatients. The late 1980s and early 1990s are seeing anexplosion in antiviral agents and in approaches to antiviraltherapy that is fueled, in part, by the AIDS epidemic. Thisarticle reviews the basis of antiviral therapy, the agentsthemselves, the problems to be solved, and prospects for thefuture.

CELLULAR AND VIRAL REPLICATION

Like antibacterial agents, useful antiviral agents musthave certain properties. They must reach their target organs,be active intracellularly as well as extracellularly, and be

metabolically stable. Most important, they must inhibit virusreplication without disturbing host cell function. Becauseviruses reproduce intracellularly and use host cell metabolicmachinery in doing so, it was thought for many years thatspecific interference with viral replication was impossible.Experience with early antiviral compounds corroboratedthis view; the drugs were either too toxic or insufficientlypotent to be of use (460). Two drugs that illustrate this wellare idoxuridine (5-iodo-2'-deoxyuridine) and trifluorothymi-dine (5-trifluoromethyl-2'-deoxyuridine) (Fig. 1). Idoxuri-dine was first synthesized by Prusoff in 1959 (363) and wassubsequently shown to inhibit a number of DNA viruses (fora review, see reference 364). When administered systemi-cally to patients, however, it did not decrease the risk ofdeath from herpes encephalitis and it caused myelosuppres-sion in almost all patients who received it (40). On the otherhand, the drug was effective and much less toxic whenadministered topically to patients with herpes keratitis (233).It is still used for this purpose. Recently, there has been aresurgence of interest in topical use of idoxuridine coupledwith dimethyl sulfoxide for treatment of herpes labialis (450).Trifluorothymidine, first developed as an antitumor agent,was found to inhibit herpes simplex virus (HSV) in vitro, butits selectivity index (ratio of drug concentration causingcellular toxicity to that needed for viral inhibition) was verylow compared with those of other agents (99) and it was notdeveloped for systemic use. Like idoxuridine, it is used fortopical treatment of herpes keratitis.

Despite their shortcomings, these drugs were important in

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ANTIVIRAL THERAPY 147

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IDOXURIDINE TRIFLUOROTHYMIDINE VIlFIG. 1. Some nucleoside analogs first used as antiviral agents.

that they demonstrated the feasibility of antiviral therapy inpatients. They also sustained interest in a continuing searchfor more selective agents. By the late 1970s, it was knownthat most human pathogenic viruses possess enzymes codedby the viruses themselves and not present in uninfected cells(327). Most of these enzymes are involved in viral nucleicacid synthesis, as discussed below. Their discovery repre-sented a major advance in antiviral therapy by making itpossible to direct efforts at finding specific inhibitors of theseenzymes rather than nonspecific inhibitors of viral growth incell culture.

Replication of viruses can be divided into several steps: (i)attachment to the cell, (ii) penetration, (iii) uncoating ofnucleic acid, (iv) transcription and translation of early (reg-ulatory) proteins, (v) nucleic acid synthesis, (vi) synthesis oflate (structural) proteins, (vii) assembly of mature virions,and (viii) release from the cell (for an example, see Fig. 2).All of these steps are potential targets for interference,although viral attachment, penetration, uncoating, assem-bly, and release closely resemble normal cellular processesand are thought to be carried out, in many instances, bycellular enzymes (210). It is at the point of nucleic acidsynthesis that viral processes diverge most from their cellu-lar counterparts and are most likely to require virus-specifiedenzymes. This is because eukaryotic cells contain double-stranded DNA and, when they replicate, make new DNAfrom the parental DNA template in the cell nucleus (Fig. 3).In addition, they transcribe mRNA from DNA and transportit into the cytoplasm, where proteins are translated. Viruses,on the other hand, may contain DNA or RNA as theirgenomic material, and the nucleic acid may be double orsingle stranded, circular or linear, and segmented or in onecontinuous piece. RNA may be either positive or negativestranded (having the same sense or direction as mRNA, andthus directly translatable, or having the opposite sense andnot directly translatable). Viruses may replicate in the nu-cleus, in the cytoplasm, or in both. Despite these differencesfrom their cellular hosts, viruses must be able to fit into hostcell synthetic pathways if they are to replicate successfully.They must present to the cell either a form of DNA that canbe transcribed directly into mRNA or a form of mRNA thatthe cell can recognize and translate into proteins (390). Manydifferent pathways have evolved by which viruses accom-plish this; some examples are shown in Fig. 3. Retroviruses,for example, carry single-stranded duplex RNA as theirgenomic material and, when infecting cells, must supply avirus-encoded reverse transcriptase to transcribe this RNA

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into cDNA which is then inserted into the host cell DNA(Fig. 2). Picornaviruses such as rhinoviruses and enterovi-ruses carry a positive single-stranded RNA that can bedirectly translated by host cell enzymes, but they mustencode an RNA replicase which allows use of the genomicRNA as a template for new negative-stranded RNA. Ortho-myxoviruses (influenza viruses), on the other hand, carry anegative-stranded RNA, and thus must supply an RNA-dependent RNA polymerase from which a plus-strandedmRNA can be made. Such unique enzymes, critical to viralreplication but unnecessary for cellular function, offer verygood targets for selective inhibition by antiviral agents. Theyare not the only enzyme targets, however.

Other enzymes such as nucleoside kinases and DNApolymerases are encoded by both cells and viruses (Fig. 4).The properties of such enzymes can differ greatly withrespect to substrate specificity, binding affinity for sub-strates, and susceptibility to inhibition by various com-pounds. These differences can be exploited in developingantiviral compounds. For example, thymidine kinases cata-lyze the first step in the preparation of pyrimidine nucleo-sides for incorporation into DNA, phosphorylation of the 5'carbon atom of the pentose ring (Fig. 4). Thymidine kinasespecified by HSV binds acyclovir much better than cellularthymidine kinase does and phosphorylates it 3 million timesfaster (235). DNA polymerases are responsible for incorpo-rating nucleotide triphosphates into growing DNA chains,and again, herpesvirus-specified DNA polymerases differfrom their cellular counterparts: they are 30 times moresusceptible to inhibition by acyclovir triphosphate than arethe alpha DNA polymerases of human origin (122). Differ-ences like these make it possible to identify compounds thatselectively inhibit viral functions. What advantage is there toviruses in encoding and carrying enzymes also made bycells? The answer is survival. Viruses carrying the extraenzymes have a wider host range and can infect cells that donot encode a critical enzyme or that express it only at acertain point in the cell cycle. HSV mutants that do notencode thymidine kinase, for example, are less capable ofestablishing reactivatable latent infections in neurons (whichare nondividing cells) than are thymidine kinase-encodingstrains (121, 142, 471).Many antiviral agents are nucleoside analogs, structures

that closely resemble the natural nucleosides used as build-ing blocks for DNA synthesis (Fig. 1 and 5). As such, thesedrugs are phosphorylated by cellular nucleoside kinases andincorporated into growing DNA chains by DNA polymer-

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ases, competing with the natural nucleosides as substratesfor both enzymes (Fig. 4). Many of the early antiviral agents,such as idoxuridine and trifluorothymidine, were equallygood substrates for both viral and cellular kinases. Eventhough they were slightly better inhibitors of viral than ofcellular polymerases (194, 365), they were activated andcapable of decreasing DNA synthesis in both infected anduninfected cells. Many of the newer nucleosides are lesstoxic, in part because there is at least one point in theirfunctional pathways which is specific for virus-infected cells.For example, acyclovir is activated only in virus-infectedcells, and zidovudine inhibits an enzyme, human immuno-deficiency virus (HIV) reverse transcriptase, not found innormal cells.Although the greatest success has been achieved by using

inhibitors of nucleic acid synthesis as antiviral agents, addi-tional enzymes are necessary for other steps in the viralreplication cycle and should be amenable to inhibition byputative antiviral compounds. Special interest in such com-pounds has been generated by the AIDS epidemic and theincreasingly obvious need to treat HIV infection with com-binations of drugs active at different sites of viral replication.Such combination therapy, it is hoped, will decrease drugtoxicity and reduce the chances of antiviral resistance de-veloping during treatment. Unfortunately, steps such as viralattachment and penetration and assembly and release arecatalyzed by cellular enzymes (210), and it has been difficultto find compounds that interfere specifically with theseevents. Nevertheless, some success has been achieved withamantadine (an inhibitor of uncoating) for management ofinfluenza, and recombinant soluble CD4 may yet proveeffective at inhibiting attachment of HIV to host lympho-cytes. Interferons, which inhibit viral mRNA transcriptionand protein synthesis, are also useful as antiviral agents. Inaddition, HIV proteases, which cleave precursor polypep-tides to form functional reverse transcriptases, are verypromising targets for selective inhibition.

ANTIVIRAL AGENTS

Amantadine and Rimantadine

The adamantanes, amantadine (1-aminoadamantane hy-drochloride) and its alpha-methyl derivative, rimantadine,are used for management of influenza A virus infections.They are cyclic amines with bulky, cagelike structuresunlike those of other known antiviral agents (Fig. 6). Theirmechanisms of action and spectra of antiviral activity areidentical, but rimantadine is metabolized differently fromamantadine, and it causes fewer central nervous system sideeffects such as insomnia and difficulty concentrating (110,514). It is also a more potent in vitro inhibitor of influenza Aviruses (431), although both drugs have been equally effec-tive in treating patients. Amantadine became available in1966; rimantadine is being considered for approval by theU.S. Food and Drug Administration.

It has been known for some time that amantadine inhibitsan early phase of viral replication (207, 232), more specifi-cally, virus uncoating (48, 381). Recent studies of avianinfluenza viruses have also demonstrated a block at a laterstage, virus maturation and assembly (184, 461). Suscepti-bility to amantadine is determined principally by the M2protein (184, 281), a virus-specified matrix protein present onthe surface of infected cells and in the virion in smallamounts (530). It has been proposed (28) that this proteinforms ion channels through which protons pass across themembranes of intracellular endocytic and exocytic vesicles.During virus uncoating, protons are transferred from theendocytic vesicle to the virion, allowing the fall in pH thatreleases free viral nucleoprotein into the cell cytoplasm.During virus assembly, protons are transferred out of theexocytic vesicle, thus maintaining the pH above the level atwhich the viral hemagglutinin, a major surface glycoprotein,would lose its structural integrity and fail to be incorporatedinto the viral envelope. Amantadine appears to block thisM2-mediated transfer of protons and thus inhibits viral

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uncoating or viral maturation or both, depending on thestrain of virus (185). At in vitro concentrations much higherthan those at which these effects occur, adamantanes inhibitother RNA viruses, including influenza B virus, andparamyxoviruses (114). With current drug formulations,these high concentrations cannot be achieved in patients,and thus the adamantanes remain useful only for the man-agement of influenza A virus infections (Table 1).Both drugs are very effective in preventing illness due to

influenza A virus. When given prophylactically during acommunity outbreak, either compound reduces the risk ofacquiring influenzal illness by 50 to 90% ( 68, 110, 161, 317,331, 500). Rimantadine has fewer side effects when used in

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this manner, although lowering the dose of amantadine alsoreduces adverse effects (378, 419). The efficacy of low-doseamantadine has not been proven in this situation, however,and the higher dose remains the prophylactic regimen ofchoice until rimantadine becomes available. Both drugs aremore effective in preventing illness than in preventing infec-tion with influenza A virus (110, 317). This may be beneficial,however, in that it allows the patient to produce protectiveantibodies without developing frank illness. Currently, theImmunization Practices Advisory Committee recommendsusing amantadine prophylactically to protect those at risk ofinfluenza complications who cannot or have not been vacci-nated (60). The drug can also be given at the same time as

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CLIN. MICROBIOL. REV.

TABLE 1. Antiviral agents currently available and their uses

Agent Route of administration Use Adult dosage

Acyclovir Oral Initial genital herpes 200 mg 5 times daily for 10 days

Ophthalmic ointment

Recurrent genital herpesSuppression, genital herpesSuppression, mucocutaneous herpes

in immunocompromised hostTreatment, mucocutaneous herpes inimmunocompromised host

Zoster in immunocompetent host

Herpes encephalitisNeonatal herpesaSevere genital herpesTreatment, mucocutaneous herpes,immunocompromised host

Suppression, mucocutaneous herpesin immunocompromised hosta

Zoster or varicella in immunocom-promised host

Initial genital herpesCutaneous herpes in immunocompro-

mised host

CMV retinitis in AIDS

HIV infection, CD4 cells <500/mm3,or symptomatic

Herpes encephalitisNeonatal herpesZoster in immunocompromised host

Herpes keratitis

Influenza A: treatmentInfluenza A: prophylaxis

Severe RSV, infants and children

Lassa fever'

200 mg 5 times daily for 5 days400 mg twice daily for up to 1 yr200 mg 3 to 5 times daily

200-400 mg 5 times daily until healed

800 mg 5 times daily for 7-10 days

10 mg/kg 3 times daily for 10-21 days500 mg/mTh 3 times daily for 10 days5 mg/kg 3 times daily for 5 days5 mg/kg 3 times daily for 7 days

5 mg/kg 3 times daily

Adult: 10 mg/kg 3 times daily for 7 days

Child: 500 mg/mrn 3 times daily for 7 days

Apply every 3 h up to 6 times daily for 7 daysApply every 3 h up to 6 times daily for 7 days

Induction: 5 mg/kg twice daily for 14-21 daysMaintenance: 5 mg/kg daily

100 mg 5 times daily

15 mg/kg daily over 12-24 h for 10 days15 mg/kg daily over 12-24 h for 10 days15 mg/kg daily over 12-24 h for 5 days

0.5 in. [1.27 cm] to eye 5 times daily for 7-21days

200 mg daily for 5-7 days200 mg daily

12-18 h daily for 3-7 days (concn, 20 mg/ml)

2-g load, then 0.5-1 g 3-4 times daily for 10days

Ophthalmic solution

Ophthalmic solution

Hepatitis B-chronic active liver dis-ease'

Hepatitis C-chronic liver disease

Condyloma acuminata (warts)

CMV retinitis

Acyclovir-resistant HSV or VZVa

Zidovudine intolerance or treatmentfailure in HIV-infected host

Herpes keratitis

Herpes keratitis

5 x 106 U daily for 4 mo

2 x 106-3 x 106 U 3 times weekly for 6 mo

1 x 106 U per wart in up to 5 warts 3 timesweekly

Induction: 60 mg/kg 3 times daily for 2-3 wkMaintenance: 90-120 mg/kg daily40-60 mg/kg 3 times daily

Tablet: 125-300 mg (as 2 tablets) 2 times daily

Powder: 167-375 mg 2 times daily

1 drop every 2 h up to 9 drops daily untilhealed

1 drop/h during day and every 2 h at night un-

til healed

a The package insert is not approved for this indication.b Square meters of body surface area.

Intravenous

Topical

Ganciclovir

Zidovudine

Vidarabine

Intravenous

Oral

Intravenous

Amantadine

Ribavirin

Oral

Aerosol

Intravenous

Interferon Subcutaneous

Intralesional

IntravenousFoscarnet

Didanosine

Trifluridine

Idoxuridine

Oral

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influenza virus vaccine to protect the patient until an anti-body response to the vaccine occurs.Both amantadine and rimantadine have been used for the

treatment of influenza. They are most effective when givenwithin the first 48 h of illness and may allow the patient toreturn to routine daily activities 1 to 2 days earlier than notreatment would (191, 475, 483, 514). Amantadine alsoappears superior to aspirin in this regard. In one comparativestudy, patients taking 3.25 g of aspirin daily became afebrilesooner but had more side effects (insomnia, nausea, ringingin the ears) than amantadine recipients, who experienced anearlier reduction in symptoms and fewer adverse reactions(528). The peripheral pulmonary airway dysfunction accom-panying influenza is also improved by amantadine (279), andthis may be important for earlier resolution in normal hostsand for minimizing disease in those with underlying pulmo-nary or cardiac conditions. The effects of therapy on thecomplications of influenza, such as pneumonia and myo-carditis, are unknown.Although drug resistance does not occur naturally among

influenza viruses (27), it can be induced by therapy, andthese resistant viruses can cause influenzal illness. Whenpatients ill with influenza were treated with rimantadine,they improved symptomatically, but 50% of them beganshedding rimantadine-resistant viruses within 4 to 6 days(177, 188). In one study, these resistant viruses were appar-ently transmitted to family members, who also became illwith influenza (188). Resistance was mapped to the M2protein (29), and subsequent studies of similarly resistantavian viruses have shown that these resistant strains aregenetically stable and equal in virulence to wild-type viruses(25). These findings raise the possibility that widespread useof adamantanes for treatment of influenza might result inantiviral pressure and selection of predominantly resistantvirus populations. To prevent the spread of resistant virus, ithas been suggested that patients be isolated or have limitedcontact with others while they are being treated for influenza(186). The effects of this and other methods to controltransmission are unknown, however. In view of these prob-lems and of the unknown effect of therapy in preventing orrelieving complications, no recommendation for therapy ofinfluenza is currently made by the Centers for DiseaseControl (60), although amantadine is approved for thispurpose (package insert).

Ribavirin

Ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carbox-amide) was first synthesized in the early 1970s as part of anintensive effort to identify new antiviral agents (517). At firstglance, it appears to be a nucleoside analog with an openpyrimidine ring (Fig. 5). Structurally (362) and functionally(458), however, it most closely resembles guanosine. Riba-virin is active in vitro against a wide variety of RNA andDNA viruses, including adenoviruses, herpesviruses, influ-enza A and B viruses (429, 517), respiratory syncytial virus(RSV) (212), bunyaviruses, arenaviruses (214), reoviruses(367), and HIV (292).The mode of action has not been clearly defined. Three

mechanisms have been proposed, and all may operate tosome extent in cells infected by different viruses. This mayalso account for the wide spectrum of activity. Ribavirinreadily diffuses into eukaryotic cells, where it is convertedby cellular enzymes to the mono-, di-, and triphosphateforms (437, 458). The monophosphate is a potent competi-tive inhibitor of IMP dehydrogenase, an enzyme essential for

the synthesis of GTP. This inhibition results in a decrease inthe cellular pools of guanine nucleotide necessary for bothcellular and viral replication (458, 459). Ribavirin inhibitscapping of viral mRNA (170, 493), a critical step in thereplication of most viruses. Its most important effect, how-ever, appears to be on the early events of viral replication.Ribavirin directly inhibits viral RNA-dependent RNA poly-merase of influenza viruses (129), and it can retard bothinitiation (54, 338, 367, 521) and elongation (129, 521) ofmRNA transcripts. It is not incorporated into the growingchain of viral nucleic acid and does not cause chain termi-nation (129, 477). Only one strain of virus, a mutant of fowlplague virus, is known to be resistant to ribavirin (215).

In addition to its antiviral properties, ribavirin has im-munoregulatory effects. In cell culture and in animals, itinhibits macromolecular synthesis and cell division (270),lymphocyte proliferation, and nucleic acid synthesis (341). Italso suppresses B lymphocytes and subsequent antibodyproduction (358) and tumor growth (357). To date, however,none of these effects has been shown to be of consequence inpatients treated with ribavirin.The major toxicities of ribavirin are anemia and embryo-

toxicity. Anemia occurs when ribavirin diffuses into eryth-rocytes and accumulates, because erythrocytes lack phos-phatases and are unable to hydrolyze (dephosphorylate) thedrug. The erythrocytes then become damaged as they ageand are removed prematurely from the circulation (52, 334).At very high doses of ribavirin in animals, bone marrowsuppression of erythroid precursors also occurs (52). All ofthese effects are reversible upon removal of the drug, but thehalf-life of ribavirin in human erythrocytes is 40 days, so theeffect is prolonged. In pregnant rodents treated with ribavi-rin, skeletal defects in the developing embryo as well as fetalresorption have been observed (242). Because of this, thedrug is contraindicated during pregnancy, and safety mea-sures must be taken by pregnant health care workers whoadminister ribavirin to patients (see below).

Ribavirin became commercially available for use as anaerosol in 1986. Both the oral and intravenous forms havebeen studied, but the drug was found to be most effectivewhen given to animals by pulmonary aerosol, so it wasdeveloped for that purpose. The drug is diluted in a reser-voir, nebulized by a small-particle aerosol generator, anddelivered to the patient via face mask, ventilator, or infantoxygen hood. Aerosolized drug can leak from the systemduring administration and may be inhaled by health careworkers. This may represent a hazard to pregnant workers,although it is not known whether the small amounts ab-sorbed into the bloodstream will damage the fetus (57).

In college students with uncomplicated influenza, aerosolribavirin reduced the duration of fever and symptoms anddecreased viral shedding (239, 291, 513). This has not beentrue of all trials and for all influenza variants, however (33,167). Because of this inconsistency and because aerosoltherapy is an expensive and cumbersome mode of therapyfor a self-limited illness, ribavirin is not often used in thissetting.

In infants with bronchiolitis due to RSV, ribavirin hasshown some effect in decreasing viral shedding, improvingoxygenation, and reducing the duration of illness (178, 179,388, 469), although questions have been raised about themethods used in treatment trials (494). In a recent trial,ribavirin decreased the duration of oxygen therapy, mechan-ical ventilation, and hospital stay in otherwise healthy in-fants with severe RSV illness (439). Nevertheless, importantquestions remain unanswered, including duration of therapy,

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response of children with underlying cardiac and pulmonarydisease, and efficacy of the drug when administered late inthe course of illness (368). Ribavirin is extremely expensive($400 per day in drug costs alone), and all children withself-limited RSV cannot be hospitalized and treated. Alongwith the possible toxicity for health care workers, theseunanswered questions indicate the great need for additionalstudies to define the optimum use of this drug for respiratoryviral disease.

Because of its in vitro activity against bunyaviruses andarenaviruses, intravenous ribavirin has been investigated fortreatment of viral hemorrhagic fevers (214). Most notablehas been the success with Lassa fever. When patients at highrisk of death from Lassa fever were treated intravenouslywithin 6 days of fever onset, the death rate of 55 to 76% inplacebo-treated patients decreased to 5 to 9% in ribavirinrecipients (293). Oral ribavirin is also beneficial againstLassa fever and is given as prophylaxis to high-risk contactsof Lassa fever patients (58). Recent small-scale studies haveshown that ribavirin crosses the blood-brain barrier well,giving drug levels in the cerebrospinal fluid that are 50 to100% of those in serum (82, 330). For this reason, it may alsobe of use in the treatment of common viral encephalitidescaused by bunyaviruses, such as La Crosse encephalitis (54,214).

Ribavirin has recently been investigated for possible use inHIV-infected patients. Although the drug given orally in highdoses appeared to delay progression to AIDS (384), manyquestions have been raised about the study methodology(39). In addition, no effects on surrogate markers of HIVprogression (CD4 counts, p24 antigenemia, viremia, or im-mune function) were found, and it is not clear that clinicallyachievable drug levels are inhibitory for viral replication(292, 385-387). In view of these problems, licensure ofribavirin for treatment of HIV is no longer being pursued inthe United States, although the drug is available in othercountries.The place of ribavirin in our armamentarium of antiviral

agents is not yet clear. Though useful in aerosol form, it iscumbersome, expensive, and perhaps toxic. Intravenousribavirin is very useful for life-threatening illness, such asLassa fever, but toxicity limits the use of this form in lesssevere diseases. Liposome-encapsulated ribavirin has beenused successfully in animal models for treatment of RiftValley fever and influenza (163, 236), and it may represent away to achieve improved drug delivery to target organswhile minimizing toxicity. Analogs of ribavirin havebeen synthesized and tested for antiviral activity. One com-pound, 5-ethynyl-1-beta-ribofuranosylimidazole-4-carboxa-mide (EICAR), was originally studied as an antileukemicagent but has now been shown to be 10 to 30 times as activeas ribavirin against RSV and influenza viruses (98). Whetherit will be clinically useful remains to be seen.

Vidarabine

Vidarabine (9-beta-D-arabinofuranosyladenine) was thefirst antiviral agent licensed for intravenous use in the UnitedStates, in 1978. It is an analog of the nucleoside adenosine(Fig. 1) and was originally synthesized and studied in theearly 1960s as an antitumor agent. Subsequently, it wasfound to be active in vitro against HSV, varicella-zostervirus (VZV), cytomegalovirus (CMV), vaccinia virus, andsome RNA tumor viruses. In animal models, it was activeagainst HSV and vaccinia virus (409).The mechanism of action has not been completely delin-

eated, but it involves phosphorylation of the nucleoside bycellular enzymes (44, 355) and incorporation into the grow-ing chains of both cellular and viral DNAs, with resultantslowing of DNA synthesis (343). Vidarabine triphosphate isalso a competitive inhibitor of DNA polymerase, both cel-lular and viral. It is more potent, however, against viralenzymes, and this potency may account for its selectiveinhibition of viral DNA synthesis (117, 417).

Vidarabine inhibits other steps in nucleic acid synthesis,such as RNA polyadenylation (393) and terminal deoxynu-cleotidyl transferase (108), but whether or not these contrib-ute to its antiviral activity is unknown. It also inhibitsS-adenosylhomocysteine hydrolase (398), an enzyme neces-sary for methylation of tRNA and mRNA and for othercellular transmethylation reactions. This inhibition results incytotoxicity for mononuclear cells and in the possible accu-mulation of biogenic amines (117), both of which maycontribute to the toxicity of this compound.

Vidarabine became available as an eye ointment in 1977and remains useful for the treatment of herpes keratitis(Table 1). Although it is also useful for the treatment of HSVand VZV in immunocompromised patients (502, 504, 507,510) and for herpes encephalitis (508, 509) and neonatalherpes (506, 511), it has been almost entirely replaced byacyclovir for these diseases. Vidarabine is difficult to use. Itis poorly soluble in water and rapidly deaminated in vivo toarahypoxanthine, a much less active compound. It musttherefore be administered continuously by the intravenousroute in large volumes of fluid. Toxicities, including nauseaand vomiting, weakness, weight loss, megaloblastosis ofbone marrow erythroid precursors, tremors, and myoclonushave been seen in a high proportion of treated patients (287,394). Acyclovir is easier to administer, less toxic, and moreactive against herpesviruses. Although vidarabine does notrequire a virus-coded thymidine kinase for activation, andthymidine kinase-deficient HSV isolates are susceptible tothe drug in vitro, vidarabine has not proven useful fortreatment of acyclovir-resistant HSV in HIV-infected pa-tients, and foscarnet is preferred (402).

Acyclovir

Acyclovir [9-(2-hydroxyethoxymethyl)guanine] has thebest therapeutic index of available antiviral agents, and it iswidely used for the treatment of herpesvirus infections. Itwas "discovered" in the mid-1970s by Elion and colleagueswhile they were screening for antiviral activity of nucleosideanalogs (410). The compound is an analog of guanosine (Fig.5), but instead of a complete ribose ring attached to thepurine base, it has an acyclic side chain. Acyclovir diffusesfreely into cells but is activated and accumulates only in cellsinfected with herpesviruses because the first step in activa-tion, phosphorylation at the 5' position of the side chain, iscatalyzed only by a virus-specified thymidine kinase and notto any appreciable extent by cellular kinases (Fig. 4) (122,159). Further phosphorylations to the diphosphate and theactive triphosphate forms are carried out by cellular en-

zymes (122, 312). During DNA replication, acyclovirtriphosphate competes with the natural substrate, dGTP, forthe viral DNA polymerase. It has a higher affinity for theenzyme, however, and is preferentially incorporated into thegrowing chain of viral DNA (122, 453). Because the 3'hydroxyl is missing from the attached acyclovir molecule,the next nucleotide cannot be attached, and DNA replicationis terminated (103, 156, 294). Furthermore, when acyclovir isbound to the DNA template in the presence of the next

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nucleotide, a tight irreversible complex is formed and thepolymerase is completely inactivated, further slowing viralDNA synthesis (103, 158, 369). Taken together, these prop-erties make acyclovir highly selective in inhibiting viralreplication while having little effect on host cell function.There is, for instance, a 3,000-fold difference between theconcentration of acyclovir needed to inhibit HSV type 1(HSV-1) and that needed to inhibit the cells in which it isgrown (122).The herpesviruses vary in their susceptibilities to acyclo-

vir. HSV-1 and HSV-2 are exquisitely susceptible, requiringmean in vitro concentrations of 0.04 and 0.4 ,ug/ml, respec-tively, for 50% inhibition of viral replication (86, 329). Thethymidine kinase of VZV does not phosphorylate acycloviras effectively, and the virus is 8 to 10 times less susceptibleto the drug than HSV (35, 86, 329). Although its DNApolymerase is very susceptible to acyclovir (452), CMV doesnot encode a thymidine kinase (133), and high drug levels (5to 25 ,ug/ml) are required for inhibition (86, 353). It is notclear that Epstein-Barr virus (EBV) encodes a thymidinekinase capable of activating acyclovir. Its DNA polymeraseis, however, very susceptible to the drug (91), and the 50%inhibitory concentrations are low (73, 278). Acyclovir has noeffect on the latent phase of any of the herpesviruses.

Acyclovir is available in three formulations: an ointment,pills or capsules, and an intravenous suspension. Systemicabsorption and other side effects of the ointment are mini-mal, but it is not very effective (see below) and has largelybeen replaced by oral formulations. Levels achieved inserum after intravenous administration are well above theinhibitory concentrations of HSV, VZV, EBV, and somestrains of CMV. With oral dosing, however, only 15 to 20%of the medication is absorbed, and levels in serum are notconsistently above the inhibitory concentrations for any ofthe herpesviruses except HSV (100).

Acyclovir is remarkably free of serious toxicity. Whengiven intravenously in high doses, it can cause a transientrise in serum creatinine that is apparently due to obstructedrenal tubules (22, 407). A reversible neurologic syndromeconsisting of confusion, lethargy, and occasionally halluci-nations and coma has also been described. This syndrome isusually seen in very ill, immunocompromised patients re-ceiving high-dose intravenous therapy (137, 253, 491). Withoral therapy, nausea, diarrhea, and headache have occasion-ally been reported. Acyclovir is not carcinogenic and ismitogenic or teratogenic only at very high levels in animals(479). It does cross the placenta, however, and thereforemust be used with caution in pregnant patients (45, 172).Acyclovir is very effective for the treatment of HSV in

otherwise healthy patients (Table 1). When given orally orintravenously, it shortens the course of initial genital herpesby one-third to one-half (46, 79, 314, 323). Recurrent genitalherpes does not respond as dramatically, even when patientsinitiate therapy themselves at the first sign of disease (323,374). This may be because recurrences normally last only afew days, and it is difficult to demonstrate a shortening of thecourse with drug therapy. Acyclovir is, however, very usefulin preventing recurrent disease. When given daily in lowdoses to patients with frequent eruptions, it suppresses themalmost completely and causes no side effects even withprolonged use (112, 230, 306, 313). It does not preventasymptomatic viral shedding (457), and transmission hasoccurred when patients were free of genital lesions (392).Topical acyclovir, a 5% ointment, is useful, though not aseffective as oral therapy, for treatment of initial genitalherpes (79, 80, 472). In recurrent disease it offers no benefit

(282, 373). Topical therapy is occasionally used in pregnantpatients who have mild genital herpes and should not receivesystemic acyclovir.

Oral treatment of herpes labialis (the common cold sore)shortens the course of illness in those patients who are proneto more severe eruptions and are able to initiate therapythemselves at the first sign of an eruption (451). When givenprophylactically to patients exposed to the sun or to artificialUV light, oral acyclovir decreased the frequency of herpeticlesions appearing within the next 2 or 7 days, respectively(448, 449) but did not affect the lesions which appearedimmediately (within 48 h) after the exposure (448). Topicaltherapy is of little benefit in otherwise healthy patients withcold sores (448, 520). In the treatment of herpes encephalitis,acyclovir has proven both more effective and less toxic thanvidarabine (434, 503). It reduces morbidity to 14% (vidara-bine reduces it to 38%), and it is now the treatment of choicefor that disease. A recent trial of acyclovir versus vidarabinefor the treatment of neonatal herpes showed neither drug tobe superior (501). Given the sample size, however, as muchas a 25% difference in morbidity and mortality could havebeen present and gone undetected.

Acyclovir has also been very useful for management ofmucocutaneous HSV in immunocompromised patients. Ad-ministered orally or intravenously, it decreases pain andviral shedding and accelerates healing (310, 425). Though notas effective, topical therapy can also be useful in this regard(505). When given suppressively to HSV-seropositive pa-tients, acyclovir greatly reduces the chances of a recurrenceduring subsequent chemotherapy (405) or transplantation(406, 418, 423, 492).VZV infection responds better to intravenous than to oral

acyclovir, probably because levels in serum after oral ad-ministration are often below the 50% inhibitory dose for thevirus. In immunocompromised patients with chickenpox orzoster, intravenous acyclovir has been very effective indecreasing dissemination and other complications (15, 326,361, 424). It can also be given orally in the post-bone marrowtransplantation period and appears to decrease the fre-quency of zoster during that time (346, 421). In otherwisehealthy patients with zoster, intravenous acyclovir de-creases acute pain and accelerates lesion healing (23, 350),but oral therapy has had only a modest effect against thisdisease (213, 296). Neither form of therapy reduces posther-petic neuralgia. Of importance, oral acyclovir decreases thefrequency of eye complications in patients with ophthalmiczoster (69, 70). In one study of otherwise healthy childrenwith chickenpox, oral acyclovir reduced the duration ofdisease by 1 day but did not influence the complication rate,days off from school, or transmission rate within the family(18). In otherwise healthy adults with chickenpox pneumo-nia, intravenous acyclovir appears to hasten recovery (175).

Despite the reduced susceptibility of CMV to acyclovir,the drug may yet prove useful in the management of CMVdisease in immunocompromised patients. Two studies, oneof bone marrow recipients (309) and one of renal allograftrecipients (17), have suggested that high-dose intravenousacyclovir can reduce the frequency of CMV infection anddisease when given suppressively in the peritransplantationperiod. The reasons for this are not clear, but may relate tothe fact that only low numbers of viruses are present earlyafter reactivation, and the small amount of active acyclovirpresent may be sufficient to limit viral replication enough toprevent clinical disease. Acyclovir therapy of establishedCMV infections in immunocompromised patients has notbeen successful (16, 489).

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Treatment of diseases due to EBV has also been disap-pointing, despite the apparent susceptibility of the virus toacyclovir. The course and symptoms of mononucleosis arenot affected by treatment, although viral shedding from theoropharynx is decreased (3, 481). On the other hand, acy-clovir does appear to be effective for treating hairy leuko-plakia, an EBV-associated condition characterized by pain-ful tongue lesions in patients infected with HIV (377).Improvement is transient, however, and the lesions recurwhen the drug is stopped.

Resistance of HSV to acyclovir has been extensivelystudied. It results from changes in the virus-specified thymi-dine kinase and/or the DNA polymerase and occurs by oneof three mechanisms: a deletion or mutation conferringinability or reduced ability to express thymidine kinase,resulting in lack of acyclovir phosphorylation (a TK- orthymidine kinase-deficient mutant) (72, 413); expression of aDNA polymerase with reduced affinity for acyclovir triphos-phate (72, 265, 413); or expression of a thymidine kinase withaltered substrate binding properties for the drug (90, 154).Both of the last two mechanisms result in lack of recognitionof acyclovir as a substrate for the enzyme. Among patientisolates, thymidine kinase-deficient mutants are most com-mon, but viruses expressing the other mechanisms have alsobeen found (49, 76, 123, 399, 426, 490).

In nature, HSV populations consist of a mixture of TK-and normal (TK+) virus variants (337). They are predomi-nantly TK+, however, because these viruses have a selec-tive advantage in being more capable of establishing latent,reactivatable infections in host sensory ganglia. They arealso more neurovirulent (121, 142, 143, 471). Under pressureof antiviral drug therapy, a population can become predom-inantly TK-, as the TK+ variants are unable to replicate.When the drug is withdrawn, the reverse occurs. In practice,resistance develops when patients are treated for prolongedperiods with acyclovir in doses that do not suppress viralreplication completely but allow "breakthrough" replicationto occur. To date, this has been seen almost entirely inimmunocompromised patients, (19, 24, 131, 220, 335). Treat-ment consists of withdrawing acyclovir and, when neces-sary, administering a drug with a different mode of action,such as foscarnet (see below). The importance of resistancefor the future of acyclovir therapy is not yet clear. Thymi-dine kinase-deficient mutants are generally not as hardy astheir TK+ counterparts. This not true, however, of mostthymidine kinase-altered and DNA polymerase-altered vi-ruses (90, 141, 142, 265). Whether resistant virus populationswill be able to establish themselves and compete withwild-type viruses remains to be seen.

Because of acyclovir's poor oral availability and lack ofeffect against some herpesviruses, other drugs are beingsought for treatment of herpesvirus infections. Famcicloviris the diacetyl ester of penciclovir, an acyclic nucleosideanalog with a long intracellular half-life (484) and goodactivity against HSV and VZV but poor oral absorption(485). Famciclovir is well absorbed and rapidly converted topenciclovir (485) and is very promising for treatment ofherpesvirus infections. 1-Beta-D-arabinofurasonyl-E-5-(2-bromovinyl)uracil, or BV-ara-U, is a thymidine analogwhich is 1,000 times more active against VZV than acyclovir(283). Cellular toxicity is seen at concentrations 1 million-fold higher than those needed to inhibit viral replication,making this drug highly selective and very promising fortreatment of VZV infections. It is currently in patient trials.

Ganciclovir

Ganciclovir, 9-(1,3-dihydroxy-2-propoxymethyl)guanine,is a nucleoside analog similar to acyclovir except that itcontains a carbon with attached hydroxyl group at the 3'position of the ribose ring (Fig. 5). It is active against all thehuman herpesviruses (139) and is up to 100 times more activethan acyclovir against human CMV (436, 474). It is also moretoxic than acyclovir and for this reason has been used onlyfor treatment of serious CMV disease in immunocompro-mised patients.

It is not clear why ganciclovir is so much more effectivethan acyclovir against CMV. In HSV-infected cells, ganci-clovir, like acyclovir, is activated by a virus-specified thy-midine kinase (37, 139, 436). In CMV-infected cells, in whichno viral thymidine kinase is induced, ganciclovir is alsophosphorylated and accumulates to much higher levels thanacyclovir (37, 151). It is removed from these cells veryslowly, persisting in stable form for several days (37). Themolecular mechanisms of activation, accumulation, and deg-radation are not known but probably account to some extentfor the difference in activity, as ganciclovir is actually a lesspotent inhibitor of viral DNA polymerase than acyclovir is(151, 286). Ganciclovir triphosphate is incorporated into thegrowing viral DNA chain and markedly slows DNA synthe-sis (285). Because the 3' hydroxyl is present on the molecule,the next incoming nucleotide can be bound to the nascentDNA chain, and ganciclovir is thus not a chain terminator(65, 285). Despite the fact that ganciclovir, like acyclovir, isa more potent inhibitor of viral than cellular polymerases(151, 436), it is more toxic than acyclovir. In vitro inhibitionof the myeloid elements of bone marrow occurs at levels inserum seen with intravenous administration of ganciclovir(443, 444). The drug is also mitogenic in mammalian cells andcarcinogenic and embryotoxic in animals (467). In humans,ganciclovir causes a reversible bone marrow toxicity inapproximately 25% of patients, a factor that frequently limitsits use (62, 208, 422).There have been no placebo-controlled trials to evaluate

the efficacy of ganciclovir. Historically controlled trials haveshown the drug to be generally useful in the management ofCMV disease in immunocompromised patients, althoughefficacy varies among different patient groups. AIDS pa-tients with CMV retinitis respond well to intravenous ther-apy, with 80% or more achieving stabilization or improve-ment in their vision (47, 74, 138, 197, 208, 217, 271). Almostall relapse, however, unless maintenance therapy is insti-tuted, and even then many patients experience breakthroughdisease or cannot tolerate the medication. These problemsand the difficulties of long-term intravenous therapy haveprompted the investigation of other modes of treatment.Intravitreal administration of ganciclovir avoids myelosup-pression and has stabilized vision in some patients (195,198). Oral therapy is also being investigated. While the oralbioavailability of ganciclovir is very poor (6 to 8% [96]),levels in serum may be high enough to inhibit some strains ofCMV (222). AIDS patients with CMV pneumonia may havea response rate as high as 60 to 80% when given intravenousganciclovir (47, 271), although strict criteria for diagnosiswere not applied in published studies. On the other hand,only 10 to 40% of bone marrow transplant patients respond,and their mortality remains high despite suppression of viralreplication and shedding by the drug (47, 83, 422). Onehypothesis for this difference is that, in bone marrow recip-ients, CMV pneumonia is an immune-mediated diseaseresulting from T-cell cytotoxic responses to viral antigens

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expressed on the surface of infected lung cells, whereas inAIDS patients, whose cellular cytotoxic responses are poor,the disease is due to direct damage to the lungs (174). Toneutralize viral antigens and prevent recognition by immuneeffector cells, high-titered CMV immunoglobulin has beenadministered with ganciclovir in bone marrow transplantpatients. Such combined antiviral and immunomodulatortherapy has increased the survival rate to 50 to 70% (125,371). In addition, it may permit a decrease in ganciclovirdosage, with an attendant decrease in bone marrow toxicity.In one recent trial, suppressive ganciclovir therapy was verysuccessful in preventing clinical disease in bone marrowrecipients who had CMV in their respiratory secretions buthad not yet developed pneumonia (411). An additionalplacebo-controlled trial has confirmed and extended thesefindings; early ganciclovir therapy in bone marrow recipientsexcreting CMV but not yet ill reduced the frequency ofCMVdisease by 93% (from 15 of 35 to 1 of 37 patients) andsignificantly improved patient survival at 6 months post-transplantation (163). In uncontrolled trials of AIDS patientswith CMV gastrointestinal disease, ganciclovir appeared toreduce diarrhea and the pain and dysphagia of esophagitis(62, 74, 109). A recent, well-controlled study of bone marrowrecipients, however, indicated no benefit in this patientgroup (372). In patients who have undergone solid-organtransplantation and developed CMV disease, there is someevidence that ganciclovir therapy improves the recovery rate(119, 180, 193) and may improve graft survival (119).

Ganciclovir resistance has been reported in three immu-nocompromised patients being treated for CMV disease(127) and was due to lack of phosphorylation of the drug bythe CMV-infected cells (452). This finding is consistent withphosphorylation of ganciclovir by a virus-induced cellularenzyme or by an enzyme that is virus encoded. In addition,a CMV strain produced in the laboratory has been found topossess two mutations which confer ganciclovir-resistance:one in the DNA polymerase gene giving rise to an alteredDNA polymerase and one at an unknown site giving rise toan inability to phosphorylate the drug (463). An HSV strainresistant to ganciclovir because of an altered DNA polymer-ase has been identified (84). A recent prospective surveyestimated that 8% of patients receiving ganciclovir for morethan 3 months developed resistant CMV (118), suggestingthat prolonged therapy may facilitate the emergence ofresistant strains. Although the importance of ganciclovirresistance is presently unknown, the three reported patientsall had progressive CMV disease, and this suggests thatresistance can be associated with therapeutic failure.

Foscarnet

Foscarnet (trisodium phosphonoformate) is a pyrophos-phate analog unlike any other antiviral agent currently in use(Fig. 6). It was developed in the late 1970s as a less toxic,more effective alternative to phosphonoacetic acid, anotherpyrophosphate analog with antiviral properties (196). TheFood and Drug Administration recently granted an indica-tion for treatment of CMV retinitis in AIDS patients. Inclinical trials, foscarnet has also proven useful for treatmentof acyclovir-resistant herpesvirus infections.

Unlike nucleoside analogs, foscarnet does not need to beactivated by cellular or viral kinases. Instead, the moleculebinds directly to the pyrophosphate-binding sites of RNAand DNA polymerases, inhibiting them in a noncompetitivefashion with respect to nucleotide substrates (328). While themechanism of inhibition is not well understood, one hypoth-

esis is that polymerase-bound foscamet forms an unstableintermediate with nucleoside monophosphates, resulting indegradation of the nucleic acids (275, 328). Both cellular andviral polymerases are affected by foscarnet, but some viralenzymes are inhibited by concentrations 1/10 to 1/2 thoseneeded for cellular enzyme inhibition. These include thepolymerases of some strains of influenza A virus, the humanherpesviruses, hepatitis B virus, and the reverse tran-scriptase of HIV (269, 328, 404, 488, 493). Foscarnet isdifficult to use. Oral bioavailability is poor (433), althoughefforts are being made to increase absorption and prolong thehalf-life by conjugation to fatty alcohols (322). Currently, thedrug is available only in intravenous formulations, and itmust be given frequently by means of an infusion pump, asthe half-life in plasma is very short (9, 433). At physiologicpH, foscarnet is highly ionized and has limited cell penetra-tion (328, 433). Levels in spinal fluid are usually about 40%of those in plasma but may vary by a wide margin (7). Up to30% of the drug may be deposited in bone, with a subsequenthalf-life of several months (432). The importance of suchdeposition, especially for bone development in children, isnot known. The major adverse effects of foscarnet are renalimpairment (present in most patients and dose limiting in 10to 23% of them), imbalances of electrolytes such as calcium,phosphate, potassium, and magnesium (101, 134, 221, 224,382, 495), and seizures (7). It appears that foscamet chelatesdivalent metal ions such as calcium, resulting in a dose-related but reversible drop in serum calcium that may besevere or even fatal (223). Penile ulcers have also been seenwith systemic therapy and may result from the localizedirritant effect of high levels of ionized foscamet in the urine(136, 168, 276, 319, 482).

In AIDS patients with CMV retinitis, foscarnet and gan-ciclovir appear to be equally effective in preventing progres-sion of disease, as assessed in clinical trials with historicalcontrols. Vision stabilized or improved in 80 to 100% ofpatients, but maintenance therapy was required, and evenso, 70% or more relapsed (134, 224, 274, 336, 495). Thepotential advantage of foscarnet in this setting is that it hasless bone marrow toxicity than ganciclovir, and it may bepossible to use it in conjunction with zidovudine. Theadditive bone marrow toxicities of ganciclovir and zidovu-dine preclude their simultaneous administration. A con-trolled trial directly comparing ganciclovir and foscamet forCMV retinitis was recently completed. Preliminary analysisconfirmed that they are equally effective in halting progres-sion and suggested that foscarnet may prolong survival by afew months in some patients. Other uncontrolled trials haveindicated that some bone marrow and renal transplant pa-tients with severe CMV pneumonia or with fever and leuko-penia may improve with foscarnet therapy. Many died,however, and in the absence of a control group, it is difficultto assess the value of therapy in these patients (4, 238, 382).

In AIDS patients who develop acyclovir-resistant HSV orVZV infections after prolonged courses of therapy, foscar-net has proven very useful (Table 1). About 80% of patientsrespond with ulcer healing and symptom resolution (63, 130,400, 401). In this setting, foscarnet is also superior tovidarabine; the rate of lesion healing is higher and there isless toxicity (402). Maintenance therapy with foscarnet isneeded, as with other antiherpesvirus agents, and is success-ful in about 70% of patients. Apparent resistance to foscar-net has developed, however, after several courses of therapyin HIV-infected patients (34) and in one bone marrowallograft recipient treated for CMV pneumonia (241). Themechanisms of resistance have not yet been determined for

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these viruses but probably involve altered DNA polymer-ases, as seen when viruses are exposed to foscarnet in vitro(102). When patients are infected with thymidine kinase-deficient, acyclovir-resistant HSV or VZV mutants, as ismost commonly the case, foscarnet is useful for therapy, asit does not require activation by thymidine kinases. Whenacyclovir resistance is due to changes in the viral DNApolymerase, however, it may be accompanied by resistanceto foscarnet, and in these cases the drug may not be useful.

Foscarnet is effective against HIV at levels achieved inpatients' serum (404, 488). In preliminary studies, it de-creased viral (p24) antigenemia and raised helper lympho-cyte (CD4) counts (30, 221, 328), but the effect was transient,and patients relapsed when the drug was stopped. The needfor intravenous administration has made it difficult to studyfoscarnet for long-term maintenance therapy in HIV infec-tion and may preclude its use in favor of more easilyadministered drugs.

Zidovudine

Zidovudine (3'-azido-3'-deoxythymidine; formerly knownas azidothymidine, or AZT), is a synthetic dideoxynucleo-side, one of a family of nucleoside analogs in which the 2'and 3' hydroxyls of the ribose ring have been replaced byhydrogens or other moieties. It was first studied as anantitumor compound and then as a drug for feline leukemiavirus, and in 1985, it was found to inhibit HIV (316). Thedrug became commercially available in 1987 and is now usedfor management of HIV infections.

Zidovudine is an analog of deoxythymidine in which the 3'hydroxyl has been replaced by an azido (N3) group (Fig. 5).The drug is activated to its mono- di-, and triphosphateforms by cellular enzymes in both HIV-infected and unin-fected cells (155). The triphosphate is a competitive inhibitorof HIV reverse transcriptase, the RNA-dependent DNApolymerase needed for transcription of viral genomic RNAinto double-stranded DNA that can be incorporated into hostcell DNA (Fig. 2). In fact, zidovudine binds to reversetranscriptase much better than does its natural competitordTTP and is thus the preferred substrate (66, 155, 454). Italso inhibits reverse transcriptase at about 1/100 the concen-tration needed for inhibition of cellular DNA polymerasealpha (66, 155, 316). Zidovudine triphosphate is incorporatedinto the growing chain of DNA, and because the azido groupoccupies the 3' hydroxyl site, additional nucleotides cannotattach and the chain is terminated (155, 454).

Zidovudine is active in vitro against mammalian and avianretroviruses at low concentrations (153) and against EBV atconcentrations 10 to 100 times those needed to inhibit HIV(277). It inhibits some bacteria of the Enterobacteriaceaefamily when they are actively dividing (124, 234).

Zidovudine is available in both oral and intravenousforms. It is absorbed rapidly and completely from thegastrointestinal tract and so is well suited to oral use (38). Italso penetrates well into the cerebrospinal fluid and is usefulfor treating central nervous system manifestations of AIDS.The drug is metabolized primarily by hepatic glucuronida-tion, and thus its metabolism may be inhibited by other drugsthat share this pathway, such as sulfa-containing com-pounds, nonsteroidal anti-inflammatory agents, and narcoticanalgesics. Probenecid, another compound that inhibitsglucuronidation, can also be used to prolong the half-life ofzidovudine (247). One of the major drawbacks to the suc-cessful use of zidovudine has been its rapid elimination andshort plasma half-life, necessitating frequent administration.

However, its intracellular half-life is considerably longer (8,155), and more convenient dosing schedules have recentlybeen proven effective. Zidovudine also crosses the placenta(497) and has recently been associated with fetal resorptionwhen administered to mice prior to and early in pregnancy(476). The importance of this for patients remains to be seen.Despite the fact that mammalian cells do not have reversetranscriptases to be inhibited by zidovudine, it is nonethelessa moderately toxic drug. This may be explained by recentobservations. Zidovudine monophosphate competitively in-hibits thymidylate kinase, a cellular enzyme that catalyzesthe conversion of nucleoside monophosphates to diphos-phates (155). As a consequence, when cells are exposed tothe drug, intracellular pools of nucleoside di- and triphos-phates decrease, and cellular DNA synthesis is slowedaccordingly (8). In addition, when zidovudine is incorpo-rated into a growing chain of cellular DNA, it causes chaintermination (8). In patients, zidovudine can cause anemiasevere enough to require transfusion or discontinuation oftherapy. Neutropenia is less frequent, but other reactionssuch as nausea and headache are common, especially athigher doses and in patients with more advanced AIDS (166,379). A myopathy characterized clinically by muscle weak-ness and anatomically by abnormal mitochondria in musclefibers has also been described (88). Patients on zidovudineappear to have a high risk of non-Hodgkin lymphoma (318,354), although whether this susceptibility is due to the drugor simply to prolonged survival in the face of profoundimmunosuppression is not yet clear. The bone marrow-suppressive effects of zidovudine are at least additive (206)and may be synergistic with those of ganciclovir (359). Fewpatients can tolerate concurrent use of these drugs.Zidovudine is useful for treatment of all stages of HIV

infection (Table 1). In patients with AIDS or AIDS-relatedcomplex, high-dose zidovudine (1,200 to 1,500 mg daily)prolongs survival, reduces the frequency of opportunisticinfections, and improves functional capacity, weight gain,and immunologic function (116, 146). Viremia or HIV (p24)antigenemia also decreases during therapy (218, 446). Al-though the survival benefit remains after 1 to 2 years oftherapy (81, 145), the other benefits tend to disappear, witha return of antigenemia and opportunistic infections and adeterioration of immunologic function. This is partly be-cause drug toxicity requires dose reductions or discontinu-ation of therapy in many patients. A recent study has shownthat a lower daily dose, 600 mg, is as beneficial as the higherdose and much less toxic, at least in nonadvanced AIDS(144). It is now the recommended dosage. As little as 300 mgdaily may be beneficial in patients with AIDS-related com-plex (75), although it is not recommended unless patients areunable to tolerate higher doses. High-dose zidovudine is stillused for treatment of HIV neurologic disease (412, 523, 527).The bone marrow-suppressive effects of zidovudine sparethe megakaryocytes and platelets, and the drug can be usedto treat HIV-induced thrombocytopenia (332, 466). Althoughzidovudine reaches high concentrations in semen (199), itdoes not appear to decrease shedding from this site (252),and this lack may have important implications for sexualtransmission of disease.

In asymptomatic or mildly symptomatic HIV patients withCD4 (helper) T-lymphocyte counts of less than 500/mm3,both high- and low-dose zidovudine delayed disease progres-sion and transiently improved immunologic function andantigenemia (147, 487). Adverse effects were also less com-mon in these patients than in those with more advanceddisease. These patients have not been followed long enough



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to determine whether zidovudine prolongs survival in earlyHIV infection. A recent cost effectiveness analysis, how-ever, indicates that zidovudine therapy in early HIV infec-tion compares favorably with other well-accepted medicalinterventions. The cost per year of life saved, estimated at$6,553 (1989 dollars), is very similar to that of counselingpatients to quit smoking (415).

Resistance of HIV to zidovudine has been seen in patientsreceiving therapy for prolonged periods (258, 267, 391).Resistance appears to develop more rapidly and to higherlevels in patients with more advanced disease and greaterviral burdens (380), a situation somewhat analogous to thedevelopment of isoniazid resistance in patients with cavitarytuberculosis and high burdens of mycobacteria. The clinicalimportance of resistance is not known; thus far, there hasbeen no correlation with individual patient responses totherapy. At the molecular level, resistance is due to specificchanges in three or four amino acid residues of the reversetranscriptase molecule (267). In patients, high-level resis-tance is associated with accumulation of multiple mutations,and it appears to develop in a stepwise fashion over time.The only cross-resistance observed has been to other 3'-azido-containing nucleosides, suggesting decreased recogni-tion of this moiety by the altered reverse transcriptase (264).

Despite rapid and remarkable advances in the develop-ment and use of zidovudine, many questions remain unan-swered. The minimum effective dose is not yet known, norare the effects of resistance and cumulative toxicity.Whether the drug prolongs survival when given early indisease remains to be seen, and whether it will prevent HIVinfection if given prophylactically after exposure is un-known, though anecdotal experience suggests that this is notthe case (263).

Didanosine

Like zidovudine, didanosine (2',3'-dideoxyinosine [ddI];Fig. 5) is a dideoxynucleoside. It became available formanagement of HIV infections in late 1991, before definitivepatient trials were completed. It is the first compound tofollow a "fast track" to Food and Drug Administrationapproval and be made available prior to completion of safetyand efficacy studies in an attempt to make promising newdrugs quickly available to desperately ill patients.

Didanosine is an analog of deoxyadenosine. It is con-verted by cellular enzymes to ddl monophosphate, then todideoxyadenosine (ddA) monophosphate, to ddA diphos-phate, and finally to ddA triphosphate (ddATP), the activeform (1, 78, 227). Like the triphosphates of other dideoxy-nucleosides, ddATP competitively inhibits HIV reversetranscriptase and acts as a chain terminator for proviralDNA (524). Human DNA polymerase alpha is relativelyresistant to ddATP, but polymerases beta and gamma aremore sensitive to it (496), perhaps accounting for some of thetoxicity seen in patients. In vitro, ddl is less potent againstHIV than dideoxycytidine (ddC) (315), but intracellularlyddATP is as active as zidovudine (344), and it has anintracellular half-life of 8 to 12 h (compared with about 3 hfor zidovudine [1, 227]). Didanosine is also active againstzidovudine-resistant HIV isolates (264).

Didanosine is available in oral form but is somewhatdifficult for patients to take correctly. At acid pH, hydrolysisoccurs at the glycosidic bond between the sugar and the basemoieties of the nucleoside, inactivating the compound. Thedrug is thus supplied as both a buffered powder to be madeinto solution and as buffered chewable tablets which must be

taken at least two at a time to provide adequate bufferingcapacity in the stomach.The major side effects have been a painful peripheral

neuropathy in 16 to 34% of patients treated to date; pancre-atitis, seen in 8 to 9% of patients and occasionally fatal (77,257, 525); and diarrhea in 18 to 34% of patients, possiblyrelated to buffering agents used in the powder (182).Didanosine is avoided in patients at high risk for pancreati-tis, such as those with a history of heavy alcohol consump-tion or previous pancreatitis, and it increases the risk ofpancreatitis when given simultaneously with intravenouspentamidine or ganciclovir. Development of pancreatitis orperipheral neuropathy requires discontinuing the drug.

In phase I uncontrolled dose escalation studies of patientspreviously treated with zidovudine, didanosine therapy re-sulted in significant rises in CD4 cell counts and decreases inp24 antigenemia (50, 77, 257, 525). Phase II controlled trialsare under way to determine whether ddI has any effect onpatient survival, time to progression of disease, or frequencyof opportunistic infections. In view of the desperate need foradditional anti-HIV therapies and because rising CD4 cellcounts are a surrogate marker for disease improvement,didanosine was approved for use in both adult and pediatricHIV-infected patients who are unable to tolerate zidovudine(usually because of bone marrow toxicity) or who experi-ence clinical or immunologic deterioration while receiving it.Zidovudine is still regarded as first-line HIV therapy. Theplace of ddl, both by itself and in combination with otheragents for HIV therapy, will need to be determined in futuretrials.

Investigational Antiretroviral Agents

Many compounds are under investigation as candidatedrugs for the management of HIV infection. It is not possibleto discuss them all, and this section will concentrate on thosewhich are especially promising or represent a new approachto therapy and for which there is adequate description in thescientific literature.The in vitro antiretroviral activity of dideoxynucleosides

other than zidovudine was first described in 1986 (315). ddC(Fig. 5) protected cells against the cytopathic effect of HIVat 1/20 to 1/50 the concentrations needed for ddA, ddl, anddideoxyguanosine, and it was the first of these to beginclinical trials. ddC is well absorbed orally, has a shorthalf-life, and penetrates the central nervous system, al-though not as well as zidovudine (526). Its phosphorylationpathway is different from that of zidovudine, and, unlikezidovudine, it is excreted by the kidneys (526). Its toxicityprofile is also substantially different from that of zidovudine.In early trials, patients were given high doses and many ofthem developed a painful peripheral neuropathy, necessitat-ing discontinuance of the drug. Decreases in p24 antigenemiaand rises in CD4 counts were also seen, however, and nobone marrow toxicity was observed (304, 526). Currently,trials are in progress to determine the efficacy of lower dosesand of dosage schedules that employ zidovudine and ddCtogether, given either simultaneously or in an alternatingfashion (43, 351, 435). Approval of ddC by the Food andDrug Administration is expected in the near future.Two other dideoxynucleosides are currently in clinical

trials. Dideoxythymidinine, also known as D4T, has goodactivity against HIV but is phosphorylated differently fromzidovudine and has less bone marrow toxicity (205, 284).Azidouridine is slightly less active against HIV than zidovu-dine, but is also less toxic to bone marrow (67, 531), and it

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OHHO oAOH

K No CH2OHICH2CH2CH" CH3

N-BUTYL-DNJ

4H o"t.0

PROTEASE INHIBITOR XVIIFIG. 7. Investigational antiretroviral agents. Ph, phenyl; tBu,

tertiary butyl; N-butyl-DNJ, N-butyl-deoxynojirimycin.

inhibits the virus very well in peripheral blood mononuclearcells. It is currently in phase I trials.

Several nonnucleoside compounds have shown excellentactivity in vitro against HIV reverse transcriptase and arecandidates for patient trials. Among the most potent andspecific are the tetrahydroimidazobenzodiazepinone (TIBO)compounds, benzodiazepine derivatives that inhibit HIVtype 1 (HIV-1) but not HIV-2 or other retroviruses. In vitro,the selectivity index of TIBO R82150 (Fig. 7) is greater than31,000, compared with 6,200 for zidovudine and 191 fordidanosine in the same cell system (339). These agents donot require phosphorylation and inhibit HIV-1 reverse tran-scriptase by an as yet unidentified mechanism. B1-RG-587(nevirapine) is a dipyridodiazepinone with properties similarto those of the TIBO compounds (249, 305). It is beginningphase I trials in the near future. A group of six-substitutedacylouridine derivatives, the HEPT [1-(2-hydroxyethoxy-methyl)-6-phenylthiothymine] congeners, are also highly po-tent and specific for HIV-1, do not require phosphorylation,and appear to interfere with reverse transcriptase by amechanism different from that of zidovudine (10, 12). Onecompound, HEPT-S, also has pharmacokinetic propertiessuitable for oral administration.

Reverse transcriptase inhibitors can prevent new DNAfrom being made in newly infected cells but they cannotprevent the reactivation of HIV from previously infectedcells, as reverse transcriptase is not involved in this process(Fig. 2). Identification of agents capable of interfering withHIV at later points in the replication cycle, and perhapspreventing reactivation, would represent a major advance inthe management of HIV infection. One such group of agentsis the HIV protease inhibitors. HIV reverse transcriptaseand other gag and gag-pol gene products are synthesized asprecursor polypeptides and must be cleaved and processedbefore they can be packaged into virions. HIV protease, anaspartic proteinase encoded by the virus, is responsible forthis processing and is essential for the proper assembly andmaturation of fully infectious HIV-1 virions. It can also be

inhibited by protease inhibitors, small peptide molecules thatmimic the natural substrate for the reaction (97) (Fig. 7).Several such compounds have been identified and are beingdeveloped for clinical use (128, 248, 383). They are highlypotent and selective inhibitors of HIV in vitro, and at leastone has been shown to have antiviral activity when added tocell cultures late (18 to 20 h) after HIV infection and inchronically infected cells (162).Another promising compound, which acts later in the HIV

replication cycle, is N-butyldeoxynojirimycin (Fig. 7). Itreduces infectious virus in vitro in acutely infected cells andeliminates HIV entirely from chronically infected cells (231).The compound works by inhibiting glycosylation of theenvelope glycoprotein gp120, thereby reducing its ability tobind to CD4 receptors and initiate new viral infection.Although glycosylation of viral glycoproteins is nonspecificand can be carried out by cellular enzymes, N-butyl-deoxy-nojirimycin is highly specific for HIV-infected cells in vitro.Phase I trials are under way to determine its clinical utility.Another approach is interference with the viral mRNA

itself. This was first proposed for Rous sarcoma virus in 1978(529) and has been vigorously pursued for the treatment ofmany diverse diseases in addition to viral infections. Itconsists of constructing small oligonucleotides that are com-plementary to specific genes or mRNA sequences (antisenseoligonucleotides). These bind to the nucleic acid, ultimatelypreventing gene expression and protein synthesis. A mole-cule antisense to the mRNA of rev, a critical regulatoryprotein of HIV, has been synthesized, and it inhibits proteinsynthesis in vitro in chronically infected cells (289). Whilethis approach is extremely exciting, several problems witholigonucleotides, including degradation by RNases, cellularpermeability, specificity, and large-scale production, mustbe solved before they can be used as therapeutic agents. Allof these problems are under active investigation (397).

It is also possible to interfere with HIV infection at its firststep, the binding of HIV to CD4 lymphocytes (Fig. 2).Recombinant, soluble CD4 (rsCD4) is the synthetic gpl20binding portion of the complete CD4 molecule (the trans-membrane and cytoplasmic portions are missing). In vitro,rsCD4 binds to gpl20 on the virion surface and preventsattachment of the virion to CD4 lymphocytes (438). Inpatients, no toxicities were seen when the compound wasadministered in phase I trials, but the half-life in serum wasvery short, and sustained changes in p24 antigenemia andCD4 cell counts were not seen (229, 414). Currently, effortsare being directed toward the construction of rsCD4-immu-noglobulin G (IgG) and rsCD4-IgM hybrid molecules thathave longer half-lives (53), may cross the placenta (53), havegreater activity (478), and may recruit antibody-dependent(51) or complement-mediated (478) immune functions todestroy infected cells. Other efforts have resulted in thecoupling of rsCD4 to toxins such as Pseudomonas exotoxinA (64) and the plant toxin ricin (473). When bound to theHIV-infected lymphocyte and internalized, these com-pounds result in cell death. The use of Pseudomonas exo-toxin has been especially effective in vitro and "cures" cellcultures of HIV infection when used in conjunction withreverse transcriptase inhibitors (6).

IMMUNOGLOBULINS

Immunoglobulins are available in three different formula-tions: an intramuscular preparation termed immune globulinor IG; an intravenous form termed IVIG; and several differ-ent intravenous preparations with high titers of antibodies to

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individual viruses. All are made from pooled human plasmaand contain predominantly IgG, though small amounts ofother globulins are also present. High-titered (hyperimmune)globulins are derived from pooled units of plasma selectedfor high antibody titers to specific viruses. IG has beenavailable for many years, but it cannot be administeredintravenously because of the tendency for IgG to formaggregates and fix complement in vivo. Recent advances inthe cold fractionation procedure used, however, have madeit possible to prevent this aggregation, and newer prepara-tions can be given intravenously. Large volumes of fluidcannot be administered intramuscularly, so the amount ofimmunoglobulin that can be given by this route has also beenlimited. It is possible to give much larger amounts by theintravenous route, although these preparations are ex-tremely costly. Regardless of route of administration, immu-noglobulins are quite safe and are associated with very fewside effects. The mechanism of action is unknown, but in alllikelihood it involves the antibodies present.As will be discussed below, immunoglobulins are more

effective when used prophylactically than therapeutically.For viruses, this is probably because the administered anti-bodies are present during the extracellular phase of infec-tion, when it is possible to neutralize or opsonize virionsbefore they enter cells and are protected from humoralimmunity.

Currently, IG is used primarily for prevention of hepatitisA. It is administered to patients within a few days ofexposure to contaminated food or to an infected person andprevents infection or chemical illness in 80 to 95% ofrecipients (176, 255). It is also given at regular intervals totravelers who will be spending prolonged periods in condi-tions of poor or uncertain sanitation (61, 518). Although IGhas not been unequivocally shown to decrease infection withnon-A, non-B hepatitis, it may be "reasonable" to adminis-ter it to persons who sustain percutaneous exposures toinfected blood (61). IG has not been studied for prevention ofhepatitis C. For prevention of measles, IG should be given topersons who have not had the disease or been vaccinatedagainst it and who are household contacts of measles pa-tients, to those who have been exposed while pregnant, andto those who are immunocompromised when exposed (59).IG does not replace vaccine for control of measles out-breaks.Hyperimmune globulins are used for postexposure pre-

vention of hepatitis B, chickenpox, and rabies. Hepatitis BIG prevents disease in 75% of persons with needlestickexposures (420). It also prevents hepatitis B surface antigencarriage in 85 to 95% of babies born to e-antigen-positivemothers (26, 61). Along with hepatitis B vaccine, hepatitis BIG is given within a few hours of birth to babies of hepatitisB surface antigen-positive mothers. Varicella-zoster IGmodifies the severity of chickenpox but does not preventinfection when given to exposed susceptible persons. Inimmunocompromised children of less than 15 years of age(many of whom have not already had chickenpox and thusare not immune), it is administered as soon as possible afterexposure to chickenpox. It is also given to babies who haveno maternal antibody, including newborns whose mothersdevelop chickenpox within 5 days before or 2 days afterdelivery, premature babies whose mothers are seronegative,and all premature babies of less than 28 weeks of gestation.Varicella-zoster IG is very expensive, the supply is limited,and its use in adults, including exposed seronegative preg-nant women, is limited to those situations in which thephysician seeks to reduce disease severity. It has not been

shown to decrease the frequency of congenital or neonatalvaricella when administered to exposed pregnant womenand, in fact, may do the opposite by making the disease lesssevere in the mother while allowing transmission to the fetus(56). Human rabies IG became available in 1975 and is madefrom the plasma of hyperimmunized human donors. It isused in conjunction with human rabies vaccine to decreasetransmission and death after exposure to rabid animals (55).CMV IG was recently approved for management of CMVinfections in renal transplant patients. When given prophy-lactically, it reduced the frequency of serious CMV diseasein seronegative recipients of seropositive kidneys, althoughit did not decrease transmission of the virus in this setting(442). In bone marrow transplant patients the use of prophy-lactic CMV IG is controversial. In two studies it decreasedinfection rates in seronegative recipients (41, 308), in one itdid not (42), and in one it decreased CMV disease severitybut not infection rates (516). These discrepancies may be dueto differences in antibody titers of the immunoglobulins or tothe fact that small numbers of patients were studied.

Intravenous immunoglobulins were originally developedfor the treatment of primary immune deficiency states. Theyhave, however, been studied and used for many otherpurposes, including treatment and prophylaxis of viral infec-tions. Preparations are available from several different man-ufacturers, and while they are frequently considered equiv-alent, both manufacturing processes and donor populationsdiffer considerably and may result in substantially differentend products. Moreover, manufacturers are not permitted topublish information about antibody titers of their products,so it is difficult to know whether preparations have equalefficacy unless they are directly compared in patient trials.As discussed earlier, IVIG improves survival when used

in conjunction with ganciclovir for treatment of CMV pneu-monia in bone marrow recipients (125, 371). In a recent trial,IVIG also decreased the frequency of graft-versus-hostdisease and interstitial pneumonia when given alone toseropositive bone marrow recipients (462). Although CMVwas not confirmed as the cause of pneumonia in this study,it is the most common cause of interstitial pneumoniafollowing bone marrow transplantation and it is associatedwith graft-versus-host disease. This suggests that IVIG maybe beneficial in this setting.Another important use of IVIG is in the treatment of

chronic enteroviral meningoencephalitis in children withagammaglobulinemia. Given intravenously, immunoglobulinin one study did not reach very high levels in the cerebro-spinal fluid, and children almost always relapsed, thoughthey had responded initially (297). When immunoglobulinwas given through an intraventricular catheter, however,50% of the children responded, and a few appear to havebeen cured of their infection (120, 297). Further studies needto be done, but intraventricular immunoglobulin appears tobe a major advance in the treatment of this devastatingillness.There has been a great deal of interest in the use of IVIG

for the management of HIV infection and its complications.IVIG itself does not contain antibodies to HIV, but it mayprovide functioning antibodies to other infectious agents inpatients who are functionally hypogammaglobulinemic de-spite having elevated serum globulin levels (261). Children,unlike adults, do not have protective antibodies from previ-ous illnesses, and they may benefit from exogenous immu-noglobulins. One large multicenter trial of IVIG therapyrecently demonstrated that symptomatic HIV-infected chil-dren with CD4 counts of greater than 200 per mm3 had

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significantly fewer serious bacterial infections and fewerhospital days than those treated with placebo (320). A similarbenefit was not seen among those with fewer CD4 cells, butthis may have been because of the small number of childrenstudied. A second trial is under way to further investigatethese findings.No preparation of hyperimmune HIV globulin is available.

A recent trial using a high-titered preparation made from theplasma of two donors with high anti-p24 antibody titersshowed that AIDS patients given the plasma had immediateclearing of p24 antigenemia, fewer symptoms, transient risesin T lymphocytes, fewer opportunistic infections, and lowerrates of HIV isolation from blood (219). Such results areintriguing but have not been confirmed.

IMMUNOMODULATORS

In the strict sense of the word, immunomodulators aresubstances that modify the response of immune competentcells through signaling mechanisms (519). Many discussions,however, including this one, include immune-based thera-pies with a direct effect on cells such as the use of specificantibodies, exogenous immune effector cells, and proce-dures such as bone marrow transplantation. Immunomodu-lators are administered in the hope of augmenting or restor-ing host immune responses to infectious agents ormalignancies.A few older agents, for instance, levamisole, isoprinosine,

and transfer factor, have been used for several years inpatients with viral infections (455). Their effects have neverbeen convincingly demonstrated, however, and they remainlargely investigational. The AIDS epidemic has rekindledinterest in immunomodulators, and with the use of recombi-nant DNA technology it has become possible to manufacturethese compounds in large quantities and to study their effectsin patients, animal models, and in vitro systems. Immuno-modulation in HIV infection (and other viral infections) canbe a two-edged sword, however. Potent immunomodulatorssuch as cytokines have the potential for increasing viralreplication and perhaps triggering the transition from latentto active infection by stimulating target cells and makingthem more capable of supporting viral infection. They mayalso induce new targets by stimulating cells otherwise non-permissive for viral infection. Last but not least, they mayworsen or cause opportunistic infections by stimulating thetarget cells for these organisms. If some of the features ofHIV disease are autoimmune in nature, it is possible thatimmunomodulators will also worsen them (519).Tumor necrosis factor alpha, interleukin 6, and granulo-

cyte-macrophage colony-stimulating factor (GM-CSF) havebeen shown in vitro to induce expression of HIV fromchronically infected cells. Interleukins 1, 2, 3, and 4 andgamma interferon do not, while alpha interferon and trans-forming growth factor beta actually down-regulate HIVexpression (135). Only two immunomodulators, alpha inter-feron and GM-CSF, are commercially available, and thisdiscussion will concentrate on them. Many other agents arein the early phases of investigation for treatment of HIVinfection. Three of these, inosine pranobex (isoprinosine),ditiocarb sodium (diethyldithiocarbamate), and IMREG-1,have been administered to patients in controlled trials andhave shown some possible short-term effects in decreasingprogression of the disease (171, 200, 342). More and betterstudies are needed, however, to establish their utility intreatment of HIV infection. Other agents such as thymichormones (21, 430), enkephalins (333), interleukin 2 (416),

and activated natural killer cells (301) and bone marrowtransplantation (262) are in earlier stages of investigation.One other intriguing approach is that proposed by Salk: theuse of inactivated HIV vaccine or its components in HIV-infected asymptomatic individuals to stimulate cytotoxicresponses to infected cells and eliminate them, preventingprogression of disease and development of full-blown AIDS(403). An early, phase I trial of this approach has shown it tobe safe and immunogenic (370). Patients were followed forless than 1 year, however, and further trials will be neces-sary to determine the effect of postinfection immunization onthe course of HIV disease.

Interferons are natural products, small proteins, or glyco-proteins that are elaborated by eukaryotic cells in responseto viral infection. In turn, they induce in other noninfectedcells biochemical changes that render these cells resistant tosubsequent viral infection. The "antiviral state" induced byinterferons is not specific with respect to infecting virus butis relatively specific with respect to species of host cell oranimal. Interferons were first described by Isaacs and Lin-demann in 1957 (216) and have subsequently been found tohave potent antiproliferative and immunomodulating effectsin addition to their antiviral properties (349). Their primaryfunction is, in fact, related to the regulation of cell growth,differentiation, and immune function (228). Interferons arecurrently being used and actively investigated for the treat-ment of malignancies as well as viral diseases. In naturethere are three types, alpha, beta, and gamma, classified bycell of origin, primary function, and other chemical andphysical properties. Alpha and beta interferons are secretedin response to viral infection and are involved in the re-sponse to it, while gamma interferon is produced by acti-vated T lymphocytes and is involved in the response toantigens and mitogens. While gamma interferon is the pri-mary immunomodulator, all interferons affect the immunesystem to some extent. The only products available com-mercially are alpha interferons, and this review will concen-trate on them.

Interferons are now known to be cytokines, hormonelikepolypeptides that play an important regulatory role in theearly nonspecific phases of the host response to microbialinvasion. They are elaborated by almost all nucleated cellsafter exposure to a variety of stimuli, including viruses, viralantigens, and double-stranded RNA. They are then secretedfrom the infected cells and attach to receptors on other,uninfected cells. After internalization, they trigger the for-mation of enzymes that, upon exposure to double-strandedRNA, degrade viral mRNA and inhibit protein synthesis,resulting in an aborted viral infection. The best studied ofthese enzymes are 2,5-oligo(A), a family of oligonucleotidesthat synthesize an activator of RNase L, an enzyme thatcleaves RNA; and protein kinase, which phosphorylates andthereby inactivates eIF-2, a protein initiation factor (228).These are not the only mechanisms by which virus infectionsare halted, however. The multiplication of HIV, for in-stance, is directly inhibited by interferons, apparently at alate stage of replication involving release of virus particlesfrom the cell membrane (356). While these mechanisms areclear-cut in vitro, the in vivo actions of interferons areundoubtedly more complex because of the effects of inter-ferons on immune functions, including stimulation of naturalkiller cells and of B-lymphocyte proliferation, inhibition oflymphocyte blastogenesis, and enhanced expression of ma-jor histocompatibility class I receptors on cell surfaces (240).Interferons are responsible for the fever, chills, arthralgias,

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and myalgias frequently seen with viral infections, and theymay actually cause immune-mediated tissue damage.Most interferons in use today are made by using recom-

binant DNA technology. They are not absorbed from thegastrointestinal tract when given orally and thus are admin-istered by intramuscular or subcutaneous injection (512).The serum half-life is short, but the antiviral state induced incells can last several days (228).The most common early adverse effect is an influenzalike

illness characterized by fever, headache, myalgias, andarthralgias. These symptoms can usually be controlled withmedication, and tolerance soon develops, so that therapycan be continued. Later, however, fatigue, anorexia, andweight loss can develop, and these often limit the use of thedrug. Other adverse effects have been described, thoughthey are much less common: bone marrow toxicity, psycho-logical abnormalities (376), and cardiac toxicities (445).Interferon neutralizing antibodies are produced in 2 to 3% ofpatients receiving systemic therapy (447). While the signifi-cance of these antibodies is not completely understood, theirpresence has not yet been associated with a diminishedresponse in patients being treated for viral infections.

Interferons were first used clinically for the managementof herpesvirus infections in immunocompromised patients.Although they were useful in controlling the complicationsof chickenpox and zoster (5, 303, 515) and in preventing thereactivation of CMV after renal transplantation (203), theyhad no effect on prevention of CMV after bone marrowtransplantation (307) and were not as effective as acyclovirfor treatment of genital herpes (256, 340). In addition, thefrequency of adverse effects was high, and they were soonreplaced by acyclovir and ganciclovir.Because the common cold is caused by a variety of

different viruses, a nonspecific agent such as interferonwould seem an ideal mode of treatment and/or prophylaxis.Leukocyte interferon was first administered intranasally forthis purpose in 1973 (302). Unfortunately, it produced a veryhigh frequency of local side effects such as nasal stuffiness,dryness, and bleeding and actually prolonged cold symptomsrather than shortening them (190). When given prophylacti-cally to exposed family members, intranasal recombinantinterferon decreased the frequency of rhinovirus colds, but ithas little effect on colds due to other viruses (115, 187), andit was again associated with very bothersome side effects. Ithas now been abandoned for this purpose.

Anogenital warts (condyloma acuminata) lend themselvesto local, intralesional therapy, and interferons may be usefulfor this purpose. Compared with placebo, they promotefaster healing and fewer recurrences both in untreatedpatients and in those with refractory warts (132, 152, 375).Side effects were less common and less severe than inpatients receiving systemic therapy, although intralesionalinterferon is absorbed systemically. Interferons used inconjunction with other local therapies such as podophyllin(113) and laser vaporization (480) also appear superior tothese agents alone. The role of intralesional interferon ther-apy in genital warts is not yet clear. Such therapy is veryexpensive, and 20 to 30% of patients still suffer recurrences.Intralesional injections are painful, limiting the number ofwarts than can be treated. Cervical warts are very difficult toinject and may not be treatable by this mode.

In adults with chronic hepatitis B, a lack of endogenousinterferon may play a role in failure to clear the acute viralinfection and in progression to chronic disease (94). Treat-ment with exogenous interferons has been under investiga-tion for several years. Earlier trials suggested that the best

results were achieved by pretreating patients with pred-nisone, stopping this treatment, and then initiating interferontherapy during the rebound from corticosteroid therapy(347). A recent well-controlled trial, however, shows thatthis approach is effective in only a small subset of hepatitispatients with minimal liver dysfunction (348). Another largersubset of sicker patients responded to long-term (4-month)treatment with interferon alone, showing improvements inliver function and in abnormal histology and disappearanceof hepatitis B e antigen, surface antigen, and DNA from theserum (348). A recent long-term follow-up study of treatedpatients indicated that many of these remissions were sus-tained for 3 to 7 years and may, in fact, represent cures of thedisease (209, 245). In total, however, only 30 to 40% ofchronic hepatitis B patients respond to interferon, and whenlower doses are given, the response rate is lower (280).Further studies are needed to better determine which pa-tients will benefit from interferon therapy and whether it willhave any effect on long-term progression of disease, onsurvival, and on the frequency of subsequent hepatocellularcarcinoma.

In recent studies of interferon for chronic hepatitis C,about 50% of treated patients responded with decreases inliver function abnormalities, hepatic inflammation, and viralRNA in serum (93, 107, 427). Six months later, 50% of thoseresponding had relapsed, resulting in a sustained responserate of only 20 to 25%. Although alpha interferon 2b has beenapproved for treatment of chronic hepatitis C (Table 1),many important questions remain about optimum dose andduration of treatment and the need for maintenance therapy(106). Better ways to identify patients likely to respond arealso needed. In view of the cost and side effects of inter-feron, it should not be routinely used in hepatitis C untilthese problems are solved.

Interferons have been known for some time to inhibitanimal retroviruses, and they were shown in 1985 to inhibitHIV (204). In latently infected cells, interferons appear toact at a late point in virus replication to inhibit virionassembly and/or release (356). In acute infection, they pre-vent new infection of cells (204) and may act at an earlierpoint in replication. In mature macrophages, interferonsappear to limit the formation of proviral DNA (246). Whenadministered to AIDS patients for treatment of Kaposisarcoma, interferon resulted in decreased p24 antigenemiaand increased CD4 cells, although there was a "rebound"increase in p24 in some patients when the drug was stopped(105, 260). A subsequent placebo-controlled trial in asymp-tomatic HIV patients confirmed the ability of interferon todecrease viremia and perhaps opportunistic infections in thispopulation (259). It also appears that interferons work bestwhen given in early infection, while the immune system isstill reasonably intact. The role of interferons, includingthose produced endogenously in HIV infection, is complex,however, and not completely understood. It may involvemechanisms by which the virus is able to avoid the effects ofthe drug, such as down-regulation of alpha interferon recep-tors on cell surfaces after prolonged exposure to these agents(272). As noted earlier, interferons also fail to cross theblood-brain barrier and can be associated with intolerableside effects, especially in those asymptomatic patients whostand to benefit the most from them (259). For these reasons,use of interferons alone for HIV infection may be proble-matic, and they are probably best used in combination withother agents such as zidovudine and other dideoxynucleo-sides that inhibit viral replication at a different stage. Invitro, alpha interferon and zidovudine are synergistic in

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inhibiting HIV (183). In early, dose-finding patient trials, ithas been possible to administer both agents together in dosesthat appear to have an antiviral effect, although bone marrowtoxicity has been dose limiting in many cases (31, 250, 254).Much work remains to be done in this area, includinginvestigation of gamma interferons for therapy of AIDS anduse of additional agents, such as CSFs to alleviate thedose-limiting toxicities of such combinations as zidovudineand interferon.CSFs are naturally occurring cytokines that stimulate the

reproduction and differentiation of granulocytes (G-CSF) orgranulocytes, monocytes, and macrophages (GM-CSF) frombone marrow precursor cells. They also enhance the effec-tiveness of mature cells by, for instance, preventing neutro-phil migration, potentiating antigen processing by macro-phages, and stimulating phagocytosis of yeast cells andbacteria (499). Both G-CSF and GM-CSF are availablecommercially and are produced in Escherichia coli or inyeast cells by using recombinant DNA techniques. Theywere originally developed for prevention and treatment ofneutropenias induced by cancer chemotherapy and bonemarrow transplantation. A recent study indicates that theyare extremely useful for this purpose, even reducing thenumber of hospital days required following autologous mar-row transplantation (321).A great deal of interest has also developed in using them to

control the complications of HIV infection, especially theneutropenias resulting from antiretroviral therapy. CSFshave no direct effect on HIV and do not affect HIV-infectedlymphocytes. In monocytes, however, GM-CSF stimulatesvirus replication in vitro (251, 345), an effect consistent withthe cell stimulatory properties of cytokines discussed earlier.If zidovudine is added to these in vitro systems, its potencyis enhanced, and much lower concentrations are required toinhibit HIV than in the absence of GM-CSF (345). This effectis probably due to enhanced drug phosphorylation by thestimulated cells, and while it may be useful in the treatmentof AIDS patients, it also raises the possibility of increasedzidovudine-induced bone marrow toxicity when both drugsare administered simultaneously. These issues have not beenresolved, but they have not prevented substantial progress inthe use of CSFs.Groopman and colleagues first showed that GM-CSF was

biologically active in raising granulocyte counts in leuko-penic AIDS patients (173) and went on to demonstrate thatthe induced neutrophils functioned normally in killing Staph-ylococcus aureus. The same investigators also identified twopatients with defective bacterial killing mechanisms (one inphagocytosis and one in intracellular killing), but these, too,appeared to be corrected by GM-CSF (14). Subsequentstudies have shown both G-CSF and GM-CSF to be veryeffective in correcting the neutropenias seen with zidovudinetherapy alone (311) or combined with interferon, and the twoCSFs have allowed treatment to continue in patients other-wise unable to tolerate it because of bone marrow toxicity(92, 408). This has been true of patients with advanced (408)as well as early (92) HIV disease. There is also preliminaryevidence that GM-CSF may ameliorate the neutropeniaassociated with ganciclovir therapy (181). The doses of CSFsneeded in AIDS patients are usually much lower than thoseused in cancer patients, and the side effects are more closelyrelated to the use of zidovudine and interferon. CSFs are,however, prohibitively expensive. In the dosages used forcancer patients, the cost is approximately $200 per day (300).Whether or not it will be lower in AIDS patients remains tobe seen. In the face of this, it is important for future studies

to identify the patients most likely to benefit from theseexpensive agents.

PROBLEMS OF ANTWIRAL THERAPY

ResistanceUnlike bacteria, viruses do not have a wide variety of

mechanisms for developing resistance to chemotherapeuticagents. They are genetically simple and metabolically inert,and changes like those seen in bacteria, such as decreaseduptake of antibiotics, acquisition of resistance plasmids, orinduction of inactivating enzymes, have not been seen.Viruses do, however, have two properties that allow them toevade potential inhibitors: they have the ability to replicateto high titers in host cells, and they can mutate very rapidly.As a consequence, most viral resistance arises from geneticmutation, giving rise to changes in either enzymes or struc-tural components of the virion. The success of this mecha-nism can be seen in cell culture, where viruses readilydevelop resistance after only a few passes in the presence ofan inhibitory agent (for a review, see reference 140). Incontrast, very few resistant viruses have been isolated fromimmunocompetent patients being treated for viral diseases(19, 126). Resistant herpesviruses are isolated from patientsimmunocompromised by cancer chemotherapy or transplan-tation, although this is relatively infrequent. In addition,most of these resistant viruses appear to have reducedvirulence and to cause predominantly indolent, non-life-threatening infections (19, 85, 428). There are however,increasing reports of AIDS patients with life-threatening orvery serious illnesses due to resistant herpesviruses (127,131, 164, 288), suggesting that severely immunocompro-mised patients may provide a milieu in which mutant virusesare not at a selective disadvantage and can prosper. Inaddition, a larger viral load creates a larger gene pool fromwhich mutations can emerge. Under these circumstances,selective pressure from antiviral agents could result in thepropagation and perhaps the transmission of resistant vi-ruses, eventually replacing wild-type susceptible popula-tions with more resistant ones.

Despite what is known about viral resistance in vitro, agreat deal remains to be learned about its importance andabout the management of patients infected with resistantviruses. A summary of unanswered questions follows.Under what circumstances does resistance arise? In gen-

eral, it seems that the greatest risk is in severely immuno-compromised patients receiving prolonged courses of anti-viral therapy, but the details of the relationship amongresistance, severity of underlying disease, and treatment areunknown. Although the herpesviruses do not become resis-tant easily in immunocompetent patients (325), influenzaviruses do (188). The reasons for this difference are notknown.What are the properties of the resistant viruses? Virulence

may be reduced, but this appears to depend on the host, atleast among herpesviruses. Rimantadine-resistant influenzaA virus strains, on the other hand, are as virulent for ferrets(464) and for people (188) as their wild-type counterparts.Whether resistant viruses can establish latency is anotherimportant but unanswered question. This ability may alsodepend on the host and the mechanism of resistance. Like-wise, little is known about transmissibility of resistant vi-ruses. To date, transmission of resistant herpesviruses hasnot been documented, but it may only be a matter of time,unless resistance is accompanied by reduced transmissibil-

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ity. Resistant influenza viruses, on the other hand, appear tobe readily transmitted, at least in a household setting (188).Another very important issue is cross-resistance amongantiviral drugs. A great deal is known about in vitro cross-resistance, and a few clinically useful patterns haveemerged, such as cross-resistance of zidovudine-resistantHIV to other azido-containing nucleosides and susceptibilityof thymidine kinase-deficient HSV to drugs not needingphosphorylation or not requiring a virus-induced enzyme forphosphorylation. A great deal remains to be learned, how-ever. At least 20 different DNA polymerase mutants havebeen found in vitro among HSV variants, for instance, andmost of them possess altered drug-binding properties. Resis-tance to one compound is usually accompanied by decreasedsusceptibility to other drugs of the same class, but predict-able cross-resistance among different classes of drugs hasalso been found and is thought to indicate overlap ofdrug-binding sites (71). Exceptions to known patterns alsoexist, further confirming the complexity of resistance due toDNA polymerase changes. Consequently, predicting cross-resistance in DNA polymerase mutants may not be possibleunless the viruses are carefully characterized.What is the result of the development of drug resistance in

the patient? As discussed above, the appearance of zidovu-dine-resistant HIV has not yet been associated with clinicaldeterioration in individual patients, although it may play arole in the reduced effectiveness of zidovudine after manymonths of therapy. Failure of herpes lesions to heal and evenserious illness are frequently due to acyclovir-resistantherpesviruses in AIDS patients, but this is not true in otherimmunocompromised patients in whom failure to heal mayor may not be due to acyclovir resistance and in whomlesions due to resistant virus may heal despite the lack ofeffective therapy (470). Rimantadine prophylaxis againstinfluenza A was ineffective in persons with household expo-sures to rimantadine-treated patients, but the influenzalillness itself (due to rimantadine-resistant influenza) wastypical and resolved in the usual self-limited fashion (188).Thus, viral resistance is clinically important in some, but notall, situations and much remains to be learned.What are the most reliable ways of identifying resistance

in the laboratory? Traditional research methods that involvepropagation of viruses in cell culture, exposure to inhibitoryagents, and measurement of subsequent changes in host cellsor in amount of virus produced are time-consuming andexpensive. They may also be unreliable in that they canselect for virus strains that grow well in cell culture but arenot necessarily representative of the virus populationpresent in the patient. It is increasingly appreciated thatviruses isolated from patients are not clonal derivativeshomogeneous in their properties but instead are heteroge-neous populations of viruses with differing drug susceptibil-ities and other properties, including the ability to grow indifferent cell lines (123, 149). As a result, new methods ofmeasuring resistance are being developed for the researchlaboratory, including use of the polymerase chain reactionfor detection of resistance genes, cell lines which allowgrowth of a broader spectrum of viral strains, and improvedmethods of nucleic acid hybridization (226, 264, 266). It ishoped that these can be adapted to the clinical laboratory sothat patients can benefit directly from the improved meth-ods.What can be done to minimize problems due to drug

resistance? As with tuberculosis, it is hoped that combina-tion therapy in HIV disease will forestall or even preventclinical manifestations of drug resistance (see below). Other

measures that have been successful in herpesvirus-infectedpatients include avoiding therapy with prolonged courses ofdrugs at "subinhibitory" levels and discontinuation of ther-apy whenever possible.

LatencyWith the possible exception of a new agent that may

"cure'" cell cultures of HIV infection (see N-butyl-deoxyno-jirimycin, above), antiviral agents are virustatic rather thanvirucidal. In vitro, such agents are most active againstactively proliferating viruses, and when these agents areremoved from cell cultures, virus replication resumes. Inpatients, a course of treatment with acyclovir does notprevent future recurrences of HSV, nor does zidovudineprevent progression of AIDS, indicating that these drugs donot eliminate these viruses when they are in the latent state.Furthermore, the presence of latent virus in treated patientscould afford the opportunity for prolonged contact betweenvirus and drug, with attendant opportunities for develop-ment of drug resistance (140). The successful treatment oflatent viral infections will depend, as it does in acute viralinfections, on the identification of specific viral processesthat can be specifically attacked by antiviral agents. Re-cently, a great deal of progress has been made in defining themolecular events associated with latent HSV infections. Agroup of RNAs, termed latency-associated transcript, hasbeen described and possibly linked to reactivation of latentHSV (201); for a review, see reference 456. Advances suchas these should eventually make it possible to identify agentscapable of interfering with viruses in the latent state.

Immunosuppression by Antiviral Agents

Because antiviral agents are virustatic but not virucidal,host immune responses remain critical to the recovery ofpatients from viral infections. As discussed above, manyantiviral agents have antiproliferative activity against rapidlydividing cells, and inhibition of host immune responses hasalways been a concern in antiviral therapy. A recent directcomparison of the effects of several antiviral agents on theproliferative responses of peripheral blood mononuclearcells from healthy individuals indicated that zidovudine,ganciclovir, and ribavirin decreased mitogenesis, while acy-clovir and didanosine had no effect (192). Another studyshowed that zidovudine, didanosine, and ddC had no inhib-itory effect on the bactericidal activity of polymorphonuclearleukocytes and possibly enhanced it (389). Further studiesare needed, but these trials demonstrate the need for iden-tifying the immunosuppressive properties of individual anti-viral agents, establishing their importance in patients, andusing this information to individualize patient therapy.

PROSPECTS FOR THE FUTURE

LiposomesLiposomes are synthetic phospholipid vesicles that can be

used as carriers of many biologic molecules, includingantitumor and antimicrobial agents, immunomodulators,toxins, and enzymes. When administered to animals orhumans, they are naturally distributed to the reticuloendo-thelial organs and cleared by phagocytic cells, especiallyblood mononuclear cells and tissue macrophages. Lipo-somes can also be targeted to specific cells by incorporatingthe appropriate antibodies into them. For these reasons,

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they are ideal agents for delivery of drugs to intracellularorganisms such as viruses. Although no patient trials ofantiviral therapy have yet been reported, animal and in vitrostudies are intriguing and encouraging. Liposomes havebeen used to increase the cellular permeability of highlyionized drugs such as foscarnet (468) and to lengthen thehalf-life of ddC in the central nervous system of rats (237).HSV-infected cells can be selectively destroyed by lipo-somes encapsulated with acyclovir and tagged with anti-HSV antibodies (324) or by mononuclear phagocytes acti-vated by liposomes encapsulated with immunomodulatorssuch as gamma interferon or macrophage-activating factor(243). Of importance, CD4-bearing liposomes interact withHIV-infected lymphocytes and deliver their contents to theinterior of these cells (87). This raises the possibility ofloading these liposomes with antiviral agents such as reversetranscriptase inhibitors and using them to deliver the drugsto the interior of HIV-infected cells. HIV-1 also fusesdirectly with negatively charged liposomes, and its infectiv-ity is thereby decreased (244), another promising approachto treatment of HIV.

Combination Therapy

Prompted by the success of combination chemotherapyfor cancer and stimulated by the need for effective treatmentof HIV infection, combination therapy has come to theforefront of antiviral treatment. The purpose is threefold: toenhance the efficacy of single-agent therapy, to minimizetoxicity by reducing individual drug dosages, and to preventor forestall the development of drug resistance. There aremany reports of drug combinations synergistic in vitroagainst HIV and other viruses. Many patient trials are alsounder way, but few have been completed and most data arepreliminary. The most promising combinations consist of anonnucleoside and a nucleoside inhibitor of HIV reversetranscriptase or of two drugs active at different sites of viralreplication. Different toxicities are also very important. InAIDS patients with Kaposi sarcoma, for instance, zidovu-dine and alpha interferon together showed early evidence ofsuppressing antigenemia more effectively than either drugalone and, possibly, of delaying drug resistance (31, 148).ddC is a reverse transcriptase inhibitor like zidovudine, butit is phosphorylated by a different mechanism and hasdifferent toxicities. When ddC is administered with zidovu-dine in an alternating regimen, less toxicity is seen than witheither agent alone at full doses (43, 351, 435). Very excitingresults have been obtained by giving GM-CSF to patientswho develop neutropenia on zidovudine-interferon regi-mens. GM-CSF rapidly alleviated the neutropenia and al-lowed patients to remain on this very effective regimen whenthey would otherwise have been unable to tolerate it (92,408). One recent trial demonstrated what appears to be anadditive effect of zidovudine and foscarnet in suppressingp24 antigenemia (225). Although it has no activity againstretroviruses, acyclovir can be added to zidovudine to controlconcomitant HSV infections. If herpesviruses, especiallyCMV, can transactivate HIV or induce cellular receptors forit, as has been shown in vitro (95, 295; for a review, seereference 273), control of herpesvirus infections may be-come an important part of HIV management. Despite theenthusiasm for combination therapy, adverse interactionsmust be closely monitored, and prospective combinations ofagents must be tested in vitro and in animals before they aregiven to patients. Ribavirin, for instance, is phosphorylatedby the same enzymes as zidovudine and in vitro inhibits its

effectiveness against HIV (11, 486). In vitro, when didanos-ine was added to zidovudine, the combination synergisticallyinhibited HIV, but at high concentrations it also additivelyinhibited bone marrow progenitor cells (111), indicating thatcareful dosage adjustment will be needed in treating patientswith this combination.

Computer-Aided Drug Design

Traditionally, the search for antiviral agents has consistedof randomly screening compounds for viral inhibitory activ-ity in cell culture, identifying a few, making structuralmodifications in them, and retesting for changes in activity.Computer-aided drug design uses X-ray crystallography todetermine the three-dimensional structures of viral macro-molecules and then employs computer simulation and so-phisticated thermodynamic computations to study atomicinteractions with other molecules and to delineate the struc-tures of those with favorable binding characteristics (290). Inthis way, the effect of structural modifications can be deter-mined and promising compounds can be identified before aninvestment is made in synthesizing and testing them. Thefirst human virus to be studied in this fashion was the humanrhinovirus. Its three-dimensional atomic structure was de-scribed by Rossmann and colleagues in 1985 (396). In 1986,the interaction of the virus with a known picornavirusinhibitor, WIN 51711, was described: the drug was boundwithin a deep depression on the virion surface and inducedconformational changes that increased stability and pre-vented uncoating of the virus (150, 441). A series of com-pounds with similar bridging properties were subsequentlysynthesized and studied (13), and some of them are currentlybeing tested in patients for the treatment of rhinovirus colds.The structure of the influenza virus hemagglutinin and itsinteraction with its cellular receptor, sialic acid, have alsobeen described and suggest that agents that would interferewith attachment of the influenza virus to cells could bedesigned (498). It has been proposed that HIV has a surfacesimilar to that of rhinoviruses and thus might also beinhibited at the uncoating step (395). DesJarlais and col-leagues (104) have recently used the structure of HIV-1protease and a computer-assisted searching program toidentify and study potential inhibitors of this enzyme. Inaddition, the structure of HIV reverse transcriptase itself isbeing studied by X-ray crystallography in the hope ofidentifying specific inhibitory compounds (268). Computer-assisted drug design is still in its infancy, and no antiviralagents have yet been designed de novo by this technique.Nevertheless, it is advancing rapidly and holds great promisefor the efficient, selective identification of new drugs.

Role of the Clinical Microbiology LaboratoryMost antiviral agents in use have a narrow spectrum of

activity, and many of them cause substantial toxicity at theusual dosages. Consequently, empiric patient therapy withantiviral agents is seldom possible, although it is a commonpractice with antibacterial agents. Identification of a specificviral pathogen is usually needed, and although antiviralsusceptibility testing is currently only necessary in referralcenters, the rising number of HIV-infected patients and theincreasing use of antiviral agents will eventually demand thatit be available in general and community hospitals as well.

Recent advances in diagnostic methodology have made itpossible to identify many common viral pathogens frompatient specimens within a few hours to a few days (440).

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Standard cell culture is still necessary for identification of allpossible pathogens if no specific virus is suspected of caus-ing a given illness. When only a single or a small number ofviruses is implicated, however, immunofluorescent or en-zyme immunoassays can frequently be performed directlyon patient specimens and can detect the presence of viralantigens within a few hours. RSV is commonly identified inthis way.

In other cases, shell vials are used to allow a period ofviral amplification before identification is attempted. Thespecimen is centrifuged onto a monolayer of cells grown ona coverslip in the bottom of a 1-dram (3.7-ml; shell) vial.Nutrient medium is added and the vial is incubated, usuallyfor 18 to 72 h. The coverslip is then removed, the cells arefixed, and, most commonly, a fluorescein-conjugated anti-body is added to detect the presence of viral antigen in thecells. HSV, VZV, CMV, and influenza viruses, as well assome others, can be identified in 1 to 3 days by using thismethod.Almost no convenient, practical methods for antiviral

susceptibility testing are available to the clinical laboratory.The plaque reduction assay, a method commonly used bythe research laboratory to measure antiviral activity (86,189), is time-consuming, cumbersome, and difficult to repro-duce. In addition, it depends on the ability of the virus togrow in a given cell line and thus may select virus popula-tions capable of replicating well in vitro but not necessarilyrepresentative of the population infecting the patient. Manyother methods have been used to quantitate viral replicationin the presence of inhibitory agents including nucleic acidhybridization (160), shell vials with immunofluorescentstaining (470), immunoperoxidase staining (211), enzymeimmunoassay (366), dye uptake assay (299), and yield reduc-tion assay (360). None of these methods has been standard-ized among laboratories, however. One method of nucleicacid hybridization for HSV susceptibility has been madecommercially available in kit form. It compares well with theplaque reduction assay and involves wicking of lysed, virus-infected cells onto membranes followed by hybridizationwith a radioiodinated DNA probe (465). Although thismethod is more adaptable to clinical laboratories than manyothers and is in use in some, 3 to 4 days are required forsusceptibility testing after the virus is isolated in cell cultureand radioisotopes, frequently a disposal problem for micro-biology laboratories, are still employed. As the demand forantiviral susceptibility testing grows, it is hoped that practi-cal diagnostic techniques will also become available.

CONCLUSIONS

Although early progress in antiviral therapy was slow,rapid advances have been made in the last decade. As ourunderstanding of viral replication increases, more and moreviral processes are being identified as possible targets forinhibition by antiviral compounds. Immunomodulators arebeing used increasingly to augment the immune response inthe treatment of viral diseases. Resistance to antiviral drugshas been noted among diverse groups of viruses but thus farhas caused treatment failure primarily in highly immunosup-pressed patients, such as those with AIDS. It is hoped thatcombination antiviral therapy, in addition to improving theeffectiveness of individual drugs, will limit the impact ofresistance on patient care. Other new approaches, such asthe use of liposomes to deliver antiviral drugs intracellularlyand the use of computers to identify potential new agentsrapidly and inexpensively, should result in increasingly safe

and effective antiviral drugs. With advances in laboratorytechnology making it possible to quickly identify virusesand, in the near future, perform susceptibility tests on them,antiviral therapy will rapidly become a routine part ofmedical care.

ACKNOWLEDGMENTS

I am indebted to Doris Hart and Sherry Hall for manuscriptpreparation; to Bruce Coary, Lourdes Aquino, and Eutiquio Chavezfor bibliographic assistance; and to Herb Comess for manuscript,graphics, and bibliographic preparation.

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