Topical ophthalmic therapy for herpes simplex virus (HSV) infections has been available since 1962 (i.e., idoxuridine, vidarabine, and trifluridine), but it is only in the past 20 years, with the advent of acyclovir, that there is relatively safe and effective systemic treatment of herpetic infections (Table 1). Other systemically administered antiviral agents include ganciclovir, valacyclovir, famciclovir, valganciclovir, foscarnet, cidofovir and interferons. The development of these agents is especially timely for the ophthalmologist in view of the occurrence of new herpetic infections such as the acute retinal necrosis (ARN) syndrome. In addition, as a result of the acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV), the ophthalmologist may be treating more severe and frequent infections caused by HSV and varicella zoster virus (VZV). A once rare retinal infection, cytomegalovirus (CMV) retinitis also occurs in these immunosuppressed patients.

Table 1. Topical Antiviral Agents for Ophthalmic Therapy

The ophthalmic uses of topical and systemic antiviral agents are discussed in this chapter. Antiretroviral agents and those agents that do not at this time have ophthalmic uses are not discussed.

MECHANISM OF ACTION, PHARMACOLOGY, AND TOXICITY

IDU is a pyrimidine analog that closely resembles thymidine. It is active against HSV and poxviruses. IDU depends for its antiviral activity on conversion to the triphosphate form, which mimics thymidine triphosphate and becomes incorporated into viral and mammalian DNA. The initial step is monophosphorylation by either cellular or virus-encoded thymidine kinase. The monophosphate is then converted to IDU triphosphate by cellular enzymes Incorporation of IDU triphosphate into viral DNA results in faulty transcription of viral proteins with inhibition of viral replication. This process is relatively selective in that thymidine kinase activity is higher in HSV-infected cells. This accounts for IDU's usefulness as a topical agent in the treatment of HSV epithelial keratitis. Due to inhibition of uninfected cells,⁸ however, the therapeutic ratio is narrow and IDU is too toxic for systemic use.⁹

IDU is relatively insoluble, penetrates the stoma poorly, and is rapidly metabolized into an inactive form. At room temperature, early preparations of IDU lost in vitro antiviral activity owing partly to inhibition by its major degradation product.^10,11 However, commercial preparations are reasonably stable at room temperature so that refrigeration is unnecessary.

Experimentally, IDU causes toxic changes in regenerating corneal epithelium that are not sufficient to result in a slower rate of epithelial wound closure. However, the toxicity does result in decreased stromal wound strength.¹² IDU in clinical use is toxic or sensitizing in 5% to 8% of patients.¹³ Its use has been associated with chronic follicular conjunctivitis, conjunctival scarring, punctate keratopathy, pseudodendrites, corneal edema and opacities, indolent ulceration, punctal and canalicular stenosis, narrowing of meibomian gland orifices, and contact dermatitis of the lids.^13–16 Topical IDU is teratogenic in rabbits.¹⁷ This may limit its use during pregnancy.

OPHTHALMIC USES

IDU was first demonstrated to be beneficial in the treatment of herpetic keratitis in rabbits and humans by Kaufman and co-workers in 1962.^1,2 Subsequent double-blind studies confirmed the efficacy of IDU treatment in acute superficial epithelial keratitis due to HSV.^3–6 Epithelial keratitis resolved in 55% to 80% of cases treated with IDU.^{2–6,18–24} IDU is most effective when used early in acute keratitis.^2–4 However, IDU does not prevent future recurrence of disease.^2,4,5 It is also ineffective in the treatment of HSV-related iritis or stromal disease.^2,5,6 This is possibly related in part to the drug's poor stromal penetration as well as to immunologic factors. A recent meta-analysis concluded that topical trifluridine, acyclovir, and vidarabine were significantly more effective than IDU for dendritic epithelial keratitis.^24a

IDU's poor solubility adversely effects its potential antiviral activity.¹⁶ It is formulated as a 0.1% solution and a 0.5% ointment. The recommended regimen for HSV epithelial keratitis is 1 drop hourly during the day and every 2 hours at night. The frequency may be reduced in half once there is substantial healing.² Alternatively, the ointment may be used every 4 hours during the day and once at bedtime. Treatment should be continued for at least 3 to 5 days after healing appears to be complete (to reduce the risk of disease reactivation²) up to a maximum of 14 to 21 days.

If a dendritic or ameboid ulcer fails to heal in 14 days, the possibilities of drug toxicity,^13–16 other disease, or viral resistance to IDU must be considered.²⁵ Resistance to IDU may result from a mutation in HSV leading to a loss of thymidine kinase or production of altered thymidine kinase.²⁶

IDU has been replaced by trifluridine, which is more potent and less toxic, for the treatment of herpetic keratitis. It is no longer generally available.

MECHANISM OF ACTION, PHARMACOLOGY, AND TOXICITY

Trifluridine differs from IDU in that a trifluoromethyl group, instead of iodine, is present at the 5-carbon position of the thymidine base (see Fig. 1).²⁸ As with IDU, its antiviral activity depends on triphosphorylation. It is first converted to an active form by way of monophosphorylation by both cellular and viral-encoded thymidine kinases. Because trifluridine monophosphate is a potent inhibitor of cellular thymidylate synthetase, less deoxythymidine monophosphate is formed for the drug to compete against for further phosphorylation. Cellular enzymes then convert trifluridine monophosphate to trifluridine triphosphate. This is incorporated into both viral and cellular DNA; however, viral DNA polymerase utilizes trifluridine triphosphate more efficiently than does host cell DNA polymerase. The incorporation of trifluridine triphosphate into viral DNA causes faulty transcription of messenger RNA and the production of abnormal viral proteins, leading to the inhibition of viral replication. Trifluirdine's relatively selective antiviral activity is due mainly to the marked increase in thymidine kinase activity in virus-infected cells.²⁸

Trifluridine is active in vitro and in vivo against HSV-1 and HSV-2^6a,29,30,31 and vaccinia³² and in vitro against CMV³³ and some strains of adenovirus.³⁴ It is more potent than IDU against HSV.²⁰

Trifluridine is ten times more soluble than IDU³⁰ and considerably more soluble than vidarabine,³⁵ enabling it to be formulated as a 1% solution. Trifluridine can penetrate the rabbit cornea and reach the aqueous, especially if the epithelium is absent.³⁶ In humans, topical trifluridine does not penetrate healthy corneas,³⁵ but significant amounts of unmetabolized drug reach the aqueous through diseased corneas.³⁷ This has not yet, however, translated into proven efficacy for the treatment of herpetic stromal keratitis or uveitis. Systemic absorption with topical use of trifluridine is negligible, and the drug is rapidly metabolized in plasma with a short half-life.³⁸

Topical trifluridine is generally well tolerated. Like IDU, it causes toxic changes in regenerating corneal epithelium but does not retard the closure of epithelial defects. It appears to decrease the strength of stromal wounds to a lesser degree than does IDU.¹² Although one might suppose that since trifluridine is relatively more selective than IDU in inhibiting cellular metabolism in viral-infected cells, it would have less chemical toxicity; however, this has not yet been conclusively demonstrated in clinical trials.^16,18–21 Toxic actions in the eye are similar to those of IDU and include punctate keratopathy (especially after 2 weeks of use), filamentary keratopathy, epithelial and stromal edema, punctal narrowing, and contact blepharodermatitis.^14,15,39 There is a possible association of chronic trifluridine usage with conjunctival cicatrization,^39a anterior segment ischemia,⁴⁰ and corneal epithelial dysplasia.^40a Intravitreal injections of up to 200 μg and vitrectomy solutions containing up to 60 μg/mL trifluridine were nontoxic to the rabbit retina, but higher concentrations caused retinal toxicity.⁴¹ Trifluridine is too toxic and mutagenic to be used systemically.^28,38,42 Although trifluridine was teratogenic when injected directly into chick embryo yolk sacs,⁴³ more importantly, topical application to the eyes of pregnant rabbits produced no teratogenic effects.¹⁷ It is, therefore, unlikely that topical trifluridine in the recommended dosages would, if used during pregnancy, cause fetal damage. Nevertheless a safe dose has not been established for the human embryo or fetus. This agent should be used cautiously during pregnancy and only if the potential benefits outweigh the potential risks. There is no cross-sensitivity of trifluridine with either IDU or vidarabine, thus allowing it to be used effectively in the treatment of herpetic keratitis in patients allergic to either of these two agents.^{19–21,44,45}

OPHTHALMIC USES

Trifluridine is the drug of choice for the treatment of HSV epithelial keratitis. It is supplied as a 1% ophthalmic solution. The recommended dosage is 1 drop every 2 hours while awake (with a maximum of 9 drops daily) until healing is complete. This is followed by 1 drop every 4 hours for 7 days (minimum of 5 drops daily) to prevent reactivation of disease.³⁹ Therapy should generally not be continued for more than 21 days. In most studies, trifluridine has successfully healed over 95% of herpetic superficial corneal epithelial ulcers within 2 weeks,^{16,18–21,39,45} despite the fact that in some studies trifluridine drops were used suboptimally (only five times daily).^18,21,37 If there is no improvement after 7 days or if reepithelialization is not complete within 14 days, the use of other antiviral therapy as well as possible drug toxicity or another diagnosis should be considered. Trifluridine is the only topical antiviral agent that has been demonstrated in a controlled study to be superior to debridement in the treatment of herpes simplex dendritic keratitis.⁴⁶

Randomized studies have demonstrated trifluridine to have a statistically significant better success rate than IDU in healing herpetic corneal epithelial disease, although the average healing time of about 6 days is similar for both drugs.^18,19 Data from the manufacturer indicate that in comparison studies trifluridine heals 96% of dendritic and 88% of geographic ulcers compared with 84% and 41%, respectively, for IDU.³⁸ Trifluridine is also superior to IDU in suppressing viral growth when concomitant corticosteroids are used.^19,21

Trifluridine is at least as effective as topical vidarabine ointment in the treatment of herpetic dendritic keratitis. Comparative studies have not demonstrated a statistically significant difference in the success rate of these two highly effective agents.^37,47,48 In the two randomized studies, however, trifluridine was administered either less frequently³⁹ or in a different formulation⁴⁷ than is currently recommended. Trifluridine was believed in one randomized study to be superior to vidarabine for the treatment of geographic ulcers.⁴⁹

Trifluridine is generally effective against IDU and/or vidarabine-resistant HSV epithelial keratitis.^{19–21,44,45,50} True clinical resistance of HSV to trifluridine is rare.^16,51 Treatment of HSV epithelial keratitis with trifluridine, as with all other antiviral agents, has no effect on the subsequent recurrence rate.⁵² Despite trifluridine's apparent benefit in experimental herpetic stromal keratitis,⁵³ there is no clinical evidence that it or any topical antiviral drug is effective in the treatment of HSV stromal keratitis or keratouveitis.^16,39 However, trifluridine cover allows topical corticosteroid therapy (which has proved beneficial in stromal keratitis) by preventing epithelial disease from developing when the drugs are co-administered for 10 weeks.⁵⁴

Trifluridine does not affect the course of adenoviral keratoconjunctivitis.⁵⁵ It is recommended for the treatment of vaccinia keratitis,^13,32,55a although there has been no conclusive demonstration of its effectiveness. This condition is now rare because vaccinia virus vaccinations were halted, but it may reappear as this vaccine is reintroduced in response to bioterrorism.

MECHANISM OF ACTION, PHARMACOLOGY, AND TOXICITY

Originally synthesized as a potential anticancer agent, vidarabine is obtained from fermentation cultures of Streptomyces antibioticus.⁵⁶ Vidarabine is a purine nucleoside analog that resembles deoxyadenosine but has an abnormal sugar (Fig. 2). It has in vitro activity against certain DNA viruses including herpesviruses, poxviruses, and probably hepatitis B virus.^6a,57–60 Cellular enzymes convert vidarabine to the triphosphate form, which acts as a competitive inhibitor of DNA polymerase. This effect is greater on herpes virus-induced than cellular DNA polymerase. The triphosphate derivative may also be incorporated into herpesvirus DNA, where it acts as a chain terminator. Unlike IDU, trifluridine, or acyclovir, vidarabine does not require viral thymidine kinase for its phosphorylation.⁶⁰ Therefore, vidarabine might be expected to have high activity against thymidine kinase–deficient mutants of HSV.^61–63 Because it does not selectively inhibit virally induced enzymes, however, there exists a potential for cellular toxicity especially at high doses.⁶⁰ Vidarabine is relatively insoluble and for ocular use is formulated as a 3% ointment. Vidarabine is rapidly deaminated to hypoxanthine arabinoside (ara-Hx), which is more soluble but has much less antiviral activity.^60,64 Topically administered vidarabine does not penetrate intact corneal epithelium, and even in diseased corneas only nontherapeutic amounts of ara-Hx can be found in the aqueous.^36,65 About 50% of an intravenous dose appears in the urine in 24 hours, mainly as ara-Hx.⁶⁶ The dosage must therefore be lowered in the presence of renal dysfunction. Because of vidarabine's poor solubility, it must be administered as a continuous intravenous infusion in large fluid volumes over 12 hours. Vidarabine and its metabolites are widely distributed in body fluids and tissues, including the brain and cerebrospinal fluid.⁶⁰ Minimally effective aqueous humour levels of vidarabine and ara-Hx were found after a few days of intravenous therapy at a dosage of 20 mg/kg/day in patients with HSV keratouveitis.⁶⁷ The recommended intravenous dose is 10 to 15 mg/kg/day for up to 10 days for life-threatening HSV infections.

Topically administered vidarabine does not retard the closure of corneal epithelial defects but weakens stromal wounds to the same degree as IDU. It is less toxic than IDU to regenerating corneal epithelium in animals.⁶⁸ Clinically, the ocular toxicity of vidarabine ointment appears to be similar to that of IDU.^22–24 Although some investigators believe that ocular toxicity is less frequent than with IDU, this remains to be proven.⁵¹ There is no cross-sensitization of vidarabine with either IDU or trifluridine.^21,22,44

The major adverse reactions with systemic use are gastrointestinal (anorexia, nausea, vomiting, and diarrhea), which occur in 10% to 15% of patients. Central nervous system disturbances occur in 2% to 10% and can be severe.^59,60,69,70 Ocular flutter has been reported in a patient with AIDS who was receiving vidarabine.⁷¹ Neurotoxicity is increased in the presence of renal dysfunction or when the drug is given in combination with either interferon^71a or the xanthine oxidase inhibitor allopurinol (owing to its inhibition of ara-Hx metabolism).⁷² Elevations in serum bilirubin and aspartate levels may occur, and hematologic toxicity occurs at higher dosages.⁵⁹ Vidarabine, given parenterally, is teratogenic in animals and must be used with extreme caution in women of child-bearing age.⁷³ Although there is minimal systemic absorption of the topical ocular preparation, this, too, should only be used in pregnancy if the potential benefits outweigh the potential risks.

SYSTEMIC USES

Vidarabine is beneficial in the treatment of HSV encephalitis⁷⁴ and in VZV infections in immunosuppressed adults^75–76a However, acyclovir is equal or greater in efficacy and is less toxic.^76a,79

Vidarabine and acyclovir are equally effective for the management of neonatal HSV infections.⁸⁰ Vidarabine is without proven benefit in the treatment of systemic CMV disease in neonates and renal transplant patients.^81–83 Vidarabine's role is that of a “back-up” drug for serious HSV and VZV infections should resistance to safer and more effective drugs occur.⁶²

OPHTHALMIC USES

Vidarabine ophthalmic ointment is highly effective in the topical treatment of HSV epithelial keratitis. It is at least as effective as IDU ointment in randomized controlled studies. Although most of these studies have revealed a higher percentage of healed ulcers with vidarabine treatment (and one demonstrated a better visual acuity with vidarabine²⁴), the differences have not been statistically significant.^22–24,84 In randomized trials, vidarabine was about as effective as trifluridine against HSV dendritic keratitis^39,47,48 but possibly less effective against geographic ulcers.⁴⁹ Vidarabine is also effective in the treatment of IDU-unresponsive HSV epithelial keratitis.^23,24 A meta-analysis concluded that vidarabine was superior to IDU and equivalent to topical acyclovir and trifluridine in relative efficacy for dendritic epithelial keratitis.^24a In common with other topical antiviral agents, it is not beneficial in the treatment of HSV stromal keratitis and/or iritis.^39,49,84 The major use of topical vidarabine, therefore, appears to be for the treatment of HSV epithelial keratitis in patients intolerant of, or unresponsive to, trifluridine. It is recommended that the 3% ophthalmic ointment be applied five times daily at 3-hour intervals. Following re-epithelialization, treatment should be continued for 7 days at a reduced dosage, such as twice daily. Therapy should not be continued for more than 21 days. If there are no signs of improvement after 7 days, or complete healing by 21 days, alternative therapy or the possibilities of drug toxicity or other diagnoses should be considered.

Topical vidarabine is of no benefit in the treatment of adenovirus keratoconjunctivitis, but it may possibly have an effect on vaccinia keratitis.^22,55a

Intravenous vidarabine has a very limited role in the treatment of ocular HSV infections, both because of the effectiveness of topical agents in HSV corneal disease and because of the superiority and relative ease of administration of acyclovir when systemic treatment is required. Abel and associates⁶⁷ believed that intravenous vidarabine gave slight improvement in HSV stromal keratouveitis, but there was no long-term follow-up. HSV retinitis in a renal allograft recipient transiently improved with the use of intravenous vidarabine in conjunction with a reduction of the patient's immunosuppressive medications.⁸⁵ In an uncontrolled trial of intravenous vidarabine for CMV retinitis in pharmacologically immunosuppressed patients, some improvement was suggested in four of seven cases. However, the beneficial effect was often transient, high doses (20 mg/kg) were required to suppress (but not eliminate) urinary viral excretion, and there were serious associated gastrointestinal, hematologic, and neurologic side effects.⁸⁶ This therapy cannot, therefore, be recommended. A case of disseminated VZV with bilateral retinitis (suggestive of the acute retinal necrosis syndrome) in an immunocompromised patient was apparently successfully treated with a combination of intravenous vidarabine and acyclovir after therapy with each agent alone had failed.⁸⁷ As in systemic disease, intravenous vidarabine for serious herpesvirus ocular disease has been replaced by safer and more effective agents.

MECHANISM OF ACTION, PHARMACOLOGY, AND TOXICITY

An acyclic analog of guanosine (see Fig. 2), acyclovir is the prototype of a generation of specific antiviral drugs that are activated by a viral thymidine kinase to become potent inhibitors of viral DNA polymerase.⁸⁸ The drug inhibits in vitro, in order of decreasing effect, HSV-1 and HSV-2, VZV, Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and CMV.⁸⁹ (In vivo it does have some activity against CMV.⁹⁰) Its in vitro activity is 160 times greater than that of vidarabine.⁹¹ Acyclovir's antiviral spectrum is, however, limited to the herpesvirus group.

Acyclovir must be phosphorylated to the nucleotide form, acyclovir triphosphate to exert its antiviral activity. It is first selectively phosphorylated to acyclovir monophosphate by viral thymidine kinase produced only in infected cells. Cellular kinases then convert acyclovir monophosphate to the triphosphate form.⁹² Acyclovir triphosphate is found in HSV-infected cells at concentrations 40 to 100 times greater than in uninfected cells.⁹³ That the drug is functional predominantly in infected cells explains its very low toxicity. Human CMV is relatively insensitive to acyclovir because it does not encode for viral thymidine kinase and is, therefore, inhibited only with a median inhibitory dose (ID₅₀) similar to that of the host's cells.⁸⁹ Acyclovir triphosphate is both an irreversible inhibitor of, and a substrate for, viral DNA polymerase⁹⁴ and has a greater affinity for viral DNA polymerase than for cellular DNA polymerase. In addition, the incorporation of acyclovir triphosphate into a growing DNA chain results in chain termination because it lacks a 3' hydroxyl group and, therefore, no attachment point for the next link. Because EBV, which does not produce herpes-directed thymidine kinase, is sensitive in vitro to acyclovir, additional mechanisms of action may exist.^95,96

Acyclovir can be administered topically (although not formulated for ophthalmic use in the United States), intravenously, and orally. The dosage is timed to achieve drug levels in the extracellular fluid that are greater than the ID₅₀ for HSV types 1 and 2 (mean, 0.1 to 1.6 μM) and VZV (mean, 3 to 4 μM).^88,89,97 Antiviral activity, however, is actually due to intracellular levels of acyclovir triphosphate. With intravenous dosing, the serum half-life is about 3 hours in adults with normal renal function. At a dosage of 5 mg/kg three times a day, serum concentrations are well above the ID₅₀ for HSV-1 and HSV-2, but trough levels fall below the ID₅₀ of many VZV isolates.⁹⁸ However, a dosage of 10 mg/kg three times a day provides trough levels sufficient for most VZV infections.^97,98 Acyclovir is 15% protein bound, and the volume of distribution is 70%, corresponding to total body water.⁹⁹ The cerebrospinal fluid level is 50% that of plasma.¹⁰⁰ Seventy percent of acyclovir is excreted unchanged in the urine through filtration and secretion⁹⁹; therefore, the dosage must be adjusted in the presence of renal failure. Acyclovir is readily hemodialyzable.^88,96

Absorption of orally administered acyclovir is slow and incomplete, with bioavailability of 15% to 30%. Peak plasma levels are reached in 1.5 to 2 hours.⁸⁹ Steady-state levels after administration of 200 mg orally every 4 hours range from 1.4 μM to 4.0 μM (mean, 2.5 μM).¹⁰¹ Although these levels are inhibitory for HSV-1 and HSV-2, they are near or below the ID₅₀ of VZV, which is one-tenth as sensitive as HSV-2 to acyclovir.^97,98 However, 800 mg. orally five times a day yields peak and trough serum levels of 6.9 μM and 3.5 μM, respectively, which have a better clinical effect on VZV.^88,102–104

Topical acyclovir 3% ophthalmic ointment has the best corneal penetration of any topical antiviral drug. It penetrates intact corneal epithelium to achieve aqueous levels well within the therapeutic range for HSV-1 and HSV-2.³⁷

Clinically significant intraocular concentrations of acyclovir are also achieved following oral or intravenous administration. When 400 mg. is given orally five times a day, tear^105,106 and aqueous¹⁰⁷ acyclovir levels are produced in excess of the ID₅₀ of HSV-1. The intravitreal acyclovir level 2 hours after an intravenous dose of 13 mg/kg was within the therapeutic range for HSV-1 and HSV-2, VZV, and EBV.¹⁰⁸ Intravitreal concentrations of 8.8 to 11.0 μM may result from intravenous acyclovir dosages of 5 mg/kg three times a day.⁹⁸ Subconjunctival injections of 25 mg result in clinically significant aqueous and vitreous levels¹⁰⁹ but cause subconjunctival crystals.

Experimentally, topical acyclovir has no detrimental effect on regenerating corneal epithelium or on the healing of epithelial or stromal wounds. Nevertheless, a compilation of published clinical trials of topical acyclovir did not discover a statistically significant decrease in ocular adverse reactions compared with the other available antiviral drugs.¹¹⁰ One randomized trial found a significantly decreased frequency of superficial punctate keratopathy in acyclovir recipients compared with IDU recipients.¹¹¹ Other, less common reported complications include burning or stinging, tearing, follicular conjunctivitis, palpebral allergy, and punctal stenosis.¹¹⁰ In patients with ARN who received acyclovir in the infusion fluid during vitrectomy at doses of 10 to 40 μg, there was no evidence of retinal toxicity, but one patient developed a posterior subcapsular cataract.¹¹²

Acyclovir is a remarkably safe drug when used systemically for periods as long as 5 years.^112a Toxic effects are predominantly associated with high doses (more than 5 mg/kg) of the intravenous formulation.¹¹³ The ρH of the intravenous formulation is 11, and concentrated solutions are caustic. Local irritation, phlebitis, and vesicular lesions may result from subcutaneous infiltration.^114,115 Such reactions can be circumvented by infusing acyclovir at a concentration no greater than 6 mg/mL.¹¹⁶ Acyclovir's major adverse effect is on renal function. This is due to crystallization and deposition of the drug in the kidneys of patients who are dehydrated or have preexisting renal insufficiency.¹¹⁷ Renal dysfunction can be avoided by infusing acyclovir slowly over 1 hour and administering 1 liter of fluid with each gram of the drug.¹¹⁶ Oral acyclovir has rarely been associated with renal dysfunction.¹¹⁸ Nausea, vomiting, and abdominal pain can occur and probably represent a direct toxic effect on the gastrointestinal tract.¹¹³ There is one report of diarrhea, presumably caused by the presence of lactose in oral acyclovir tablets, which responded to oral lactase administration.¹¹⁹ Rare reports of central nervous system toxicity or psychiatric disturbances have occurred, mainly in association with the use of other neurotoxic agents or in the presence of renal disease.^{118,120–124} Hypersensitivity reactions, typically transient maculopapular rashes near infusion sites, occur in less than 1% of patients.¹¹⁶ Acyclovir can be incorporated into DNA, which has raised some concern over its possible mutagenicity. There is no significant evidence that acyclovir is a carcinogen.^125,126 At much higher than clinically relevant doses, acyclovir has been teratogenic in animals,¹²⁷ but other animal studies indicate that it is not a significant teratogen.^88,128 Although there is no clinical evidence indicating teratogenicity,¹²⁹ acyclovir does cross the placenta¹³⁰ and its safety in pregnant women or in neonates has not been established.¹³¹

SYSTEMIC USES

Acyclovir is safe and effective for most HSV and VZV infections. It is both less toxic and more efficacious than vidarabine in the treatment of HSV encephalitis.^78,79 It can reduce mortality from 70% to nearly 20%. The usual dosage for HSV encephalitis is 10 mg/kg every 8 hours for at least 10 to 14 days.¹³² Acyclovir is comparable to vidarabine in the treatment of neonatal HSV infections⁸⁰ but is easier to administer. A number of placebo-controlled, double-blind clinical trials have demonstrated the therapeutic efficacy of acyclovir in the treatment of primary genital HSV infections.^133–136 Oral and intravenous treatment are superior to topical treatment.¹³⁴ The usual oral dosage is 200 mg five times daily or 400 mg three times daily for 10 days.

Oral acyclovir for 5 days is only modestly effective in treating genital or orolabial HSV recurrences in immunocompetent adults.^137,138 However, chronic oral acyclovir reduces the frequency of recurring genital HSV infection.^138a Doses of 400 mg twice daily are convenient and well tolerated.^112a,139,140 Unfortunately, following completion of acyclovir therapy, patients may return to their previous pattern of recurrent infection. Topical acyclovir 5% cream^140a slightly decreases the duration of an episode of orolabial herpes. Oral acyclovir started within 3 days of onset of herpetic gingivostomatitis in young children significantly shortens the course of the disease.^140b

Systemic acyclovir in various regimens can successfully prevent and treat mucocutaneous HSV infections in immunosuppressed patients.^141–147 However, recurrences commonly occur following the cessation of therapy.

Acyclovir is also of established benefit and preferable to vidarabine in the treatment of VZV infections in immunocompromised patients when given intravenously for 7 days at a dosage of 10 to 12 mg/kg every 8 hours.^{77, 148–152}

The indications for using acyclovir to treat VZV infections in immunocompetent adults and children with nonophthalmic disease are less obvious. Intravenous acyclovir benefits adults when administered within 72 to 96 hours of the onset of symptoms.^150,152 Oral acyclovir, given as 400 mg five times a day, is clinically ineffective in VZV infections in immunocompetent patients.^102,153 However, higher doses of up to 800 mg five times a day have had some benefit when initiated within 48 to 72 hours of exanthem and are of proven efficacy in treating herpes zoster ophthalmicus (HZO).^153–158 A meta-analysis of 4 placebo-controlled trials of oral acyclovir 800 mg. 5 times daily for 7 or 10 days concluded that acyclovir accelerates pain resolution, especially in those aged 50 or older.^158a Treatment should be strongly considered for those over 50 years of age or with moderate to severe pain and definitely for ophthalmic zoster. Some consider therapy optional in young patients with uncomplicated disease.

Studies suggest that high-dose oral acyclovir, if given within 24 hours of exanthem, reduces the severity and duration (by 1 day) of primary varicella infections (chickenpox) in normal children,^159,160 adolescents,^160a and adults.¹⁶¹ It is not known if this affects the subsequent risk of herpes zoster or if it is cost-effective to treat all patients to shorten slightly the duration of a generally self-limited disease. Treatment should be strongly considered in older patients, who tend to have more severe disease than young children.¹⁶¹ The American Academy of Pediatrics recommends the treatment of varicella with oral acyclovir (20 mg/kg to a maximum of 800 mg 4 times a day) in patients over 13 years of age, children receiving aerosolized corticosteroids, and children older than one year with chronic cutaneous or pulmonary conditions.^161a Treatment of infected household contacts might also be considered.^161b

Prophylactic high-dose intravenous or oral acyclovir may reduce the likelihood and severity of CMV infections in CMV-serononegative renal and CMV-seropositive bone marrow–transplant recipients.^162,163 Trials of acyclovir in the treatment of established CMV infections, on the other hand, have shown no consistent benefit in immunosuppressed patients.^164–167

In acute systemic EBV infections (e.g., infectious mononucleosis), acyclovir temporarily suppressed oropharyngeal EBV replication and excretion. The slight clinical benefit, however, does not justify the routine use of acyclovir for this condition.^168,169 High-dose oral acyclovir can cause temporary regression of EBV-induced oral hairy leukoplakia in HIV-infected patients.¹⁷⁰

Although there is some evidence that Bell's palsy may result from inflammation of the facial nerve in the temporal bone caused by herpes simplex virus,¹⁷¹ a definitive benefit from oral acyclovir remains controversial. A randomized controlled study demonstrated a modest but statistically significant benefit from acyclovir 200 mg 5 times a day for 5 days plus oral prednisone, compared to prednisone alone.¹⁷² The acyclovir group was 1.22 times more likely to have a good recovery, but 17% of patients were lost to follow-up. A recent meta-analysis concluded that acyclovir combined with prednisone is safe and possibly effective in improving outcomes in Bell's palsy.^172a

OPHTHALMIC USES

Herpes Simplex Virus Infection

Although not commercially available in the United States, topical acyclovir in a 3% ointment is superior to IDU^111,173,174 and equivalent to vidarabine^175–178 or trifluridine^179,180 in the topical treatment of HSV epithelial keratitis.^24a Although able to penetrate the cornea, it does not prevent stromal disease from developing during the treatment of acute epithelial disease.^175,177,178 Oral acyclovir, given as 400 mg five times a day, is equivalent to topical acyclovir^105,106,181 in the treatment of HSV dendritic ulceration. Ninety percent of orally treated patients in one study had healing of dendritic ulcers in a median of 5 days.¹⁰⁶ In another study, 200 mg five times a day healed epithelial keratitis within 5 to 21 days in 18 of 19 patients with concomitant stromal keratitis or uveitis.¹⁸² In most cases of HSV epithelial keratitis, a topical antiviral drug, such as trifluridine, would be preferable to the use of a systemic agent. Although not approved for this use, oral acyclovir may be considered in certain situations.^16,183 An oral agent might be more effective in young children, the elderly, the disabled, or others in whom the use of an eye dropper is difficult or impossible, or as an alternative for patients suffering from topical antiviral ocular toxicity. In addition, it may be a useful adjunct to topical trifluridine for the treatment of HSV keratitis in eczema herpeticum.¹⁸⁴ In small children, oral acyclovir may be especially useful as an adjunct to topical antivirals (which are diluted by children's tears). A small, retrospective study of oral acyclovir in children demonstrated healing of epithelial keratitis in all patients (6 of whom also were receiving topical antivirals). It also prevented recurrent disease in those children receiving topical corticosteroids for immune stromal keratitis while they remained on full doses of oral acyclovir.^184a

Prophylactic oral acyclovir is of apparent utility following penetrating keratoplasty in herpetically infected patients for the prevention of HSV reactivation during postoperative corticosteroid therapy.¹⁸³ Although acyclovir cannot eliminate ganglionic latency, it may reduce viral shedding in this high-risk situation^185–187; in a rabbit model, it significantly lowered the incidence of keratitis.¹⁸⁵ A statistically significant benefit of prophylactic oral acyclovir in decreasing the recurrence rate of herpetic keratitis after penetrating keratoplasty for herpes simplex keratitis was found in a small randomized trial¹⁸ (at doses of 800 or 1000 mg daily) and in a larger retrospective study (using 400 mg twice daily).¹⁸⁹ Oral acyclovir seems safe and effective for this indication when used for a year or more.^188–190 As in other situations, the prophylactic effect does not persist once acyclovir is discontinued. Although a large randomized placebo-controlled prospective trial would be needed to confirm these results, this is not likely to be done in view of the proven benefit of acyclovir in preventing herpetic ocular disease in other circumstances.

There has been interest in oral acyclovir for the treatment of herpetic stromal disease and/or keratouveitis. Both active viral proliferation and immunogenic mechanisms appear to play important roles.¹⁹¹ Topical corticosteroids, which are required to suppress the latter, may trigger or exacerbate viral replication.^192,192a,193 In general, topical antivirals used alone have been disappointing in the treatment of stromal keratitis.^16,191 Topical acyclovir with a topical corticosteroid may be of possible benefit.^194,195 Sanitato and associates¹⁹⁶ found the combination of topical and oral acyclovir without the use of topical corticosteroids to be ineffective in the treatment of 17 patients with disciform edema or necrotizing stromal keratitis.

HEDS Studies

In an effort to clarify these and other issues in therapy for herpetic stromal keratitis and iritis, including prevention of recurrent disease, the Herpetic Eye Disease Studies (HEDS) were initiated. These are a series of randomized, prospective, double-masked placebo-controlled multicenter clinical trials that have arrived at important conclusions concerning the use of oral acyclovir. HEDS determined that there is no clinical benefit to a 10-week course of adjunctive oral acyclovir for treating HSV stromal keratitis in patients receiving concomitant topical corticosteroids and trifluridine.¹⁹⁷ Similarly, the addition of a 3-week course of oral acyclovir to topical trifluridine treatment of acute HSV epithelial keratitis did not prevent the subsequent development of stromal keratitis or iritis over the following year.¹⁹⁸ For the treatment of HSV iridocyclitis, there was a strong suggestion of clinical benefit from a 10-week course of oral acyclovir 400 mg 5 times daily as an adjunct to topical corticosteroids and trifluridine (50% treatment failures with acyclovir vs. 68% with placebo).¹⁹⁹ Because of low enrollmentt, this study was stopped prematurely, providing an insufficient number of patients to reach a statistically significant conclusion. There is, however, a clear-cut benefit from long-term suppressive oral acyclovir in preventing recurrent HSV epithelial keratitis and stromal keratitis.^200,201 Seven hundred and three immunocompetent patients with prior episodes of ocular HSV disease (blepharitis, conjunctivitis, epithelial or stromal keratitis, or iritis) within the past year but no currently active disease, were randomized to oral acyclovir 400 mg twice daily or a placebo for 12 months. The cumulative recurrence rate of any ocular HSV was significantly reduced from 32% to 19% by acyclovir. The benefit was greatest in those with the most prior episodes. The benefit in preventing stromal keratitis (cumulative probability 14% with acyclovir vs. 28% with placebo), however, was solely in patients with a prior history of stromal keratitis (mainly because the risk is otherwise so low). An additional benefit was the reduction in the cumulative probability of nonocular (primarily orofacial) HSV disease from 19% to 36%. As expected, there was no lasting benefit once oral acyclovir was discontinued, but neither was there a rebound in the rate of HSV disease.

In summary, oral acyclovir 400 mg. five times daily can, in certain situations, be substituted for topical antiviral agents in the treatment of herpetic keratitis. It is of no benefit as short-term adjunctive therapy with topical agents for acute HSV epithelial or stromal disease, but is of likely benefit as adjunctive treatment of HSV iridocyclitis (in which case long-term suppressive therapy should also be considered). It is of proven benefit as long-term suppressive therapy for at least 1 year at a dosage of 400 mg twice daily. However, because HSV epithelial disease is normally responsive to topical therapy, one might consider reserving this for patients with a history of stromal disease, frequent recurrences, or immunosuppression. While there have not been studies in a randomized controlled trial for these indications, one would expect oral valacyclovir or famciclovir to be of at least comparable efficacy, with the advantage of less frequent administration.

Intravenous acyclovir has been used successfully to treat HSV retinitis in an otherwise healthy adult.²⁰² Neither acyclovir nor ganciclovir was beneficial in a fatal case of ascending encephalomyelitis with retinitis and optic neuritis due to herpes B virus infection contracted from a monkey bite or scratch.²⁰³

Herpes Zoster Ophthalmicus

Herpes zoster ophthalmicus (HZO) accounts for 10% to 25% of cases of zoster dermatitis.^203a Topical acyclovir alone has given variable results in studies of immunocompetent patients with HZO.^204–208 Although some series have suggested a possible benefit of topical acyclovir on epithelial keratitis,^204–206 randomized controlled studies comparing topical acyclovir with topical corticosteroids have yielded conflicting results.^205,207 Some authors suggest that topical corticosteroids may prolong the late inflammatory ocular complications.²⁰⁵ Acyclovir ointment has been of variable benefit in treatment of chronic herpes zoster keratitis in patients with AIDS unresponsive to systemic acyclovir.^209,209a

High doses of oral acyclovir (600 to 800 mg five times a day) have been found effective in reducing the ocular complications of keratitis and uveitis in HZO.^{154,156,157,210,211} This represents a major therapeutic advance in therapy for a disease for which only palliation was previously available.

Cobo and co-workers^156,157 performed a placebo-controlled clinical trial of 71 immunocompetent patients with acute HZO presenting within 1 week of onset of skin lesions and who did not receive oral or topical corticosteroids. They demonstrated that oral acyclovir, at a dose of 600 mg five times a day for 10 days, ameliorated the cutaneous signs and symptoms and decreased the ocular complications. The effect on cutaneous disease, including acute pain, occurred predominantly in patients treated in the first 72 hours, but the incidence and severity of inflammatory ocular complications were reduced even when treatment was begun later independent of initial severity of disease. Compared with placebo, oral acyclovir significantly reduced the incidence of pseudodentritiform keratopathy (from 31% to 14%), stromal keratitis (56% to 25%), and anterior uveitis (56% to 19%). There was no effect on episcleritis or on the development of corneal hypesthesia or neurotrophic ulceration. It was postulated that although the 600-mg dose was beneficial, it may have been near the threshold for effect.¹⁵⁵ The persistence of virus-productive disease was evidenced by the development in some patients of new dermatomal lesions and skin microdissemination as well as the recovery of virus from skin lesions as late as 14 days.¹⁵⁷ An 800-mg dose might have been even more beneficial, since it gives peak and trough serum levels above the ID₅₀ of VZV and has been effective and well tolerated.^{103,104,153,158} Other investigators^210,211 in randomized studies found that the 800-mg dose given five times daily without corticosteroids for 7 to 14 days reduced chronic ocular complications. One randomized study determined that this dosage given for 7 days was just as effective as 14 days of treatment²¹¹; another randomized study of non-ophthalmic zoster found no additional benefit of 21 days over 7 days of therapy.²¹² Although clinical trials have demonstrated the effectiveness of treatment within 72 hours of rash onset,²¹³ patients may still benefit from later treatment if new vesicles are appearing.^157,161b There has been only a single retrospective study that concluded that acyclovir did not reduce ocular complications.²¹⁴ The preponderance of evidence, however, indicates that high-dose oral acyclovir does reduce the frequency of ocular complications.^{157,158b,210,211,215,216,216a} Furthermore, as noted previously, a meta-analysis of placebo-controlled trials of oral acyclovir 800 mg 5 times daily,^158a which included one trial of patients with HZO,²¹⁰ confirmed that it shortens the duration of acute pain. A recent chart review of patients with HZO in Olmsted County provides further support for early routine systemic viral therapy. While not randomized or controlled, this study indicated that antiviral therapy may reduce the likelihood of neurotrophic keratitis.^216a The addition of oral corticosteroids to acyclovir remains controversial. It has not been rigorously studied in HZO. In non-ophthalmic zoster, there appears to be a modest effect on reducing acute (but not chronic) pain.^212,217 One study found that the combination improved short-term quality of life measures in patients over 50, compared to placebo.²¹⁷

It has not yet been adequately demonstrated that acyclovir lessens the development of post-herpetic neuralgia., This complication is most common in those older than the age of 50 and especially those aged more than 80.²¹⁸ Neither 600 mg five times daily for 10 days nor 800 mg five times daily for 7 days had an effect on the incidence, severity, or duration of post-herpetic neuralgia.^157,158 In two other placebo-controlled trials (one of HZO), 800 mg given five times daily for 10 days decreased post-herpetic neuralgia at 1 to 3 months but not at 4 to 6 months.^153,210 A recent literature review found marginal evidence that antivirals prevent post-herpetic neuralgia.²¹⁹ Although systemic corticosteroids have been advocated to prevent post-herpetic neuralgia,²¹⁴ placebo-controlled trials failed to demonstrate a long-term benefit from adding oral corticosteroids to acyclovir.^212,217,220

In summary, oral acyclovir therapy is indicated for all immunocompetent patients with HZO at a dosage of 800 mg five times a day for 7 to 10 days.^210,211,216 The newer drugs valacyclovir and famciclovir are at least as effective, with the advantage of simpler dosing.^221–223 Whether this treatment prevents chronic, life-disruptive post-herpetic neuralgia and whether the addition of oral corticosteroids provides additional benefit cannot be answered definitively at this time. Corticosteroids may be considered in patients older than 60 years of age who have no risk for corticosteroid toxicity.^158b

Herpes zoster infections may be more frequent and severe in immunosuppressed patients with an increased brisk of cutaneous and visceral dissemination of encephalomyelitis.²²⁴ Intravenous, high-dose acyclovir therapy^{77,148–150,152} is beneficial in these patients. In patients with AIDS or HIV seropositivity, HZO may be the first indication of underlying immunosuppression.^225,226,226a To prevent central nervous system complications, intravenous acyclovir may be considered in high-risk patients with HZO before obtaining the results of HIV testing.²²⁷ There is some evidence that immediate high-dose oral acyclovir administered before the development of these complications may be of benefit.²²⁸ There is not, however, sufficient information to recommend this approach.^224,228 One must be cautious in using oral acyclovir to treat patients with AIDS because of possible malabsorption.²²⁹ Retinitis in association with or following herpes zoster may occur in patients with AIDS.^230–233 It can resemble ARN, but the response to intravenous acyclovir treatment is variable. Long-term oral-maintenance acyclovir may be appropriate following intravenous acyclovir therapy of herpes zoster in AIDS patients.^233a

Acute Retinal Necrosis Syndrome

In view of the evidence implicating VZV and HSV as etiologic agents of ARN, acyclovir is a logical therapy.^234,235 Pepose and Biron²³⁶ determined the ED₅₀ of VZV recovered from the vitreous of a patient with ARN (5.3 μM). Such serum and vitreous levels are achievable with the current intravenous dosage of acyclovir for ARN^108,237 but are difficult to maintain with oral therapy.¹⁰³

Acyclovir given intravenously allows more rapid resolution of the retinitis^{234,237–239} and has become the mainstay of therapy. Because of the relatively uncommon occurrence of this syndrome, a randomized placebo-controlled trial has not been performed. In the first large reported series of treated patients, Blumenkranz and associates²³⁷ used intravenous acyclovir (1500 mg/m²/day in three divided doses) for 7 to 21 days, with an average of about 10 days. The average dose was 945 mg every 8 hours. Regression began in about 4 days and was complete on the average in about 1 month. Three of 13 eyes retained 20/30 or better vision and eight could see 20/400 or better. Also, no eye had visual loss due to progressive retinitis or optic neuropathy after 2 days of therapy. In unilateral cases, acyclovir reduced the risk of fellow eye involvement.^237–241 Despite acyclovir therapy, the progression of vitritis is common, possibly owing to immunologic processes. Unfortunately, acyclovir does not reduce the incidence of retinal detachment.²³⁷ However, some investigators have proposed that the use of acyclovir in the “mild type” of ARN may lessen the risk of retinal detachment.^239–242

The current recommended treatment of ARN is with intravenous acyclovir, 1500 mg/m²/day in three divided doses for 7 to 10 days. It is suggested that oral acyclovir (800 mg five times daily) be continued for 6 to 14 weeks after intravenous treatment, as this is the period of greatest risk of bilateral involvement.^234,241 It is reasonable to substitute oral valacyclovir or famciclovir for oral acyclovir at the conclusion of intravenous therapy.^243–245 In unresponsive cases, the addition of intravitreal injections of ganciclovir and/or foscarnet have been of reported benefit.²⁴⁶ Aspirin and prednisone may be useful adjuncts,^234,237,247 but prednisone should not be used until after the initiation of acyclovir therapy.²³⁴ Successful acyclovir therapy of ARN without the use of systemic corticosteroids was accomplished in an immunocompetent patient.²³⁸ Early prophylactic vitrectomy with intravitreal infusion of acyclovir in doses of 10 to 40 μg, in addition to intravenous acyclovir, has given variable results.^112,237,248 Although selected patients might benefit, this therapy cannot be recommended routinely.²³⁷

Intravenous acyclovir as monotherapy is ineffective in the progressive outer retinal necrosis (PORN) syndrome caused by VZV in profoundly immunosuppressed AIDS patients. The visual prognosis is guarded with any attempted treatment.^232,233,249 There is some evidence that early combination antiviral therapy may improve the outcome, with the combination of ganciclovir and foscarnet seemingly better than acyclovir-containing regimens.^250,251

Epstein-Barr Virus Infection

Both acute and chronic EBV infections have been loosely associated with ocular inflammatory disease.²⁵² Experimentally, intraocular levels of acyclovir are therapeutic for EBV infection after subconjunctival, but not topical, administration.¹⁰⁹ There are only a few case reports of acyclovir use for presumed ophthalmic EBV infection. Corneal lesions and conjunctivitis resolved in one case of infectious mononucleosis treated with topical acyclovir.²⁵³ However, stromal keratitis associated with EBV infection has responded to topical corticosteroids without the use of acyclovir.^254,255 One patient had no recurrences of presumed EBV keratitis during or after 6 months of oral acyclovir treatment,²⁵⁶ but this may represent the natural course of the disease. Wong and associates²⁵⁷ reported three cases of bilateral uveitis in patients with chronic EBV disease. Two patients had an improvement in systemic symptoms with the use of intravenous acyclovir; one of these had lessened intraocular inflammation with the addition of topical acyclovir plus topical and systemic corticosteroids. Another patient with chronic EBV infection with interstitial pneumonitis and papilledema was treated with intravenous and oral acyclovir.²⁵⁸ Although the systemic symptoms improved, there was no mention of the response of the optic disc edema. These reports suggest a possible beneficial effect of acyclovir, but further studies are required to determine the role of this drug in treating the ocular manifestations of EBV infection.

Cytomegalovirus Infection

There are no well-documented cases of successful treatment of CMV retinitis with acyclovir. Although regression of CMV retinitis in patients with AIDS has been reported with the use of acyclovir and zidovudine,²⁵⁹ this was believed to represent improved immunologic function caused by the anti-HIV effect of zidovudine in improving CD4 lymphocyte counts. High-dose intravenous acyclovir plus oral zidovudine was of dubious benefit in minimally delaying the recurrence of CMV retinitis in patients with AIDS that was previously treated with ganciclovir.²⁶⁰

RESISTANCE

There are at least three mechanisms of resistance to acyclovir. The most common mutation is loss of synthesis of viral thymidine kinase so that acyclovir is not phosphorylated to its active form.⁸⁹ A second type of mutation induces thymidine kinase with altered substrate specificity that phosphorylates thymidine but not acyclovir. Finally, a mutation of the viral DNA polymerase gene induces altered DNA polymerase that is not sensitive to inhibition by acyclovir triphosphate.

Acyclovir-resistant HSV and VZV mutants are uncommon in immunocompetent patients.^229,261 Isolates of HSV-1 in the United Kingdom obtained from 40 primary ocular infections in immunocompetent patients showed reduced sensitivity in 7.5% and acyclovir-resistance in 2.5%. Sensitivity to IDU and vidarabine was retained.²⁶² A second British study, however, found no resistance of HSV-1 viruses, although one HSV-2 isolate was resistant in vitro to all antiviral agents tested.²⁶³ Resistance to acyclovir is becoming more common in immunodeficient patients.^229,264 This is especially so in patients with AIDS receiving chronic therapy with acyclovir.^{61,229,265–267} Although many thymidine kinase-deficient HSV mutants appear less neurovirulent and less efficient in establishing ganglionic latency,²⁶⁸ they may cause progressive and severe mucocutaneous disease in immunocompromised patients, especially those with AIDS.^{61,62,264,267} Some of these patients have been successfully treated with foscarnet or cidofovir which do not rely on phosphorylation by thymidine kinase.^61,269–271 Continuous intravenous infusion of high-dose acyclovir has also been used successfully in some patients.^272–273

Acyclovir-resistant VZV has caused hyperkeratotic skin lesions in HIV-infected patients after long-term oral acyclovir suppressive therapy.²²⁹ The viral isolates had deficient or altered thymidine kinase function. Subtherapeutic doses or inadequate courses of acyclovir may have been factors in the development of acyclovir resistance in these cases. Foscarnet may be effective in treating acyclovir-resistant VZV.²⁷⁴

MECHANISM OF ACTION, PHARMACOLOGY, AND TOXICITY

Following oral administration and absorption, valacyclovir is nearly completely hydrolyzed to the active moiety acyclovir and L-valine (an essential amino acid) via first-pass intestinal and hepatic metabolism. Its antiviral activity, pharmacodynamic properties, and toxicity are, therefore, essentially those of acyclovir.^275–277 Valacyclovir, unlike acyclovir, is a substrate for a sterospecific transporter and is wellabsorbed through the gut wall.²⁷⁸ This results in a bioavailability of acyclovir from oral valacyclovir three- to five-fold higher than that of oral acyclovir, ranging from 54% to 70%.^{222,277–281} Peak acyclovir concentrations averaging 5.65 μg/mL are achieved 1.75 hours after a single oral dose of 1000 mg of valacyclovir.²⁷⁸ Systemic acyclovir exposure (serum area under the curve, or AUC) values after oral valacyclovir 1000 mg three times daily and 2000 mg four times daily are similar to those after intravenous acyclovir 5 mg/kg and 10 mg/kg three times daily, respectively.^277,278,282 Food does not affect valacyclovir administration.²⁷⁷ The mean plasma elimination half-life of acyclovir after oral valacyclovir administration is 2.62 to 3.13 hours, consistent with that of intravenous acyclovir.^277,278,281 Less than 1% of administered valacyclovir is recovered in the urine, being excreted mainly as acyclovir.^278,281 As with acyclovir, dosage modification is required with renal but not with hepatic impairment.²⁷⁷

Valacyclovir is administered only orally. It is well tolerated, with a toxicity profile similar to that of acyclovir. In comparative studies with oral acyclovir in immunocompetent patients, adverse events have been mild and infrequent; the most common events reported with either drug were nausea, headache, and diarrhea.^{221,222,277,280} In patients treated with valacyclovir or acyclovir for HZO, the most frequent adverse events were vomiting (5% and 3%, respectively) and facial edema (2% and 5%, respectively).²²¹ High doses of valacyclovir have been associated with hallucinations, confusion, gastrointestinal complaints, and nephrotoxicity (especially in severely ill HIV-infected patients).^{277,281,283–285} As with acyclovir, neurotoxicity is more likely in the presence of renal failure, reinforcing the need for dosage adjustment with renal dysfunction.²⁸⁶ An important caveat is that long-term (>90 days) high-dose (2 g four times daily) valacyclovir in patients with advanced AIDS was associated with the occurrence of thrombotic microangiopathy (thrombotic thrombocytopenic purpura/hemolytic uremic syndrome).²⁸⁵ Although this finding has not been reported in subsequent studies of patients (including HIV-infected patients) receiving lower doses (up to 1000 mg/day) for long-term-HSV suppression,²⁸⁷ this regimen should be avoided for extended periods in severely ill HIV-infected patients. Aseptic meningitis occurred after a single 1000-mg dose in an elderly patient.²⁸⁸

As with acyclovir, there is no clinical evidence of teratogenicity, but available data is insufficient to provide definitive guidelines for the use of valacyclovir in pregnancy or neonates.^280,289

SYSTEMIC USES

Valacyclovir is used for the same indications as acyclovir, which is its active moiety. The excellent bioavailability of acyclovir from valacyclovir allows for less frequent oral dosing, which may improve patient compliance.

For initial genital HSV infection, valacyclovir 1000 mg. twice daily for 10 days was as effective as oral acyclovir 200 mg 5 times daily.²⁹⁰ Patient-initiated treatment of recurrent genital HSV infection with valacyclovir 500 mg. or 1000 mg twice daily for 5 days was as effective and safe as oral acyclovir.²⁹¹ In patients with less frequent recurrences, valacyclovir dosage of 500 mg daily for 3 days can also be effective.²⁹² Valacyclovir 500 mg once daily is also effective and safe for chronic suppression of genital HSV infection; however, in HIV-infected patients or those with frequent recurrences, 500 mg twice daily is preferred,^280,293

For the treatment of herpes labialis, valacyclovir given as 2 doses of 2000 mg in 1 day modestly shortens the duration of an episode by 1 day and is more convenient than alternate regimens.²⁹⁴

Valacyclovir (1000 mg 3 times daily) has also been demonstrated in immunocompetent patients in randomized comparative trials to be at least as effective as oral acyclovir (800 mg 5 times daily) for treatment of herpes zoster.^221,222,277 Additionally, it accelerates the resolution of pain,²²² at least in non-ophthalmic herpes zoster²²¹ measured as either zoster-associated pain or post-herpetic neuralgia. There is no additional benefit of 14 days' over 7 days' treatment.^222,277 In randomized double-blind trials, the benefit of valacyclovir was present whether treatment was begun within 48 or 72 hours of rash onset.^213,221,222 An observational study found a benefit on pain cessation even when therapy was delayed beyond 72 hours.²⁸³ It is reasonable to treat patients presenting after 72 hours with skin lesions still forming, as this signifies VZV replication.²⁷⁷ Valacyclovir 1000 mg 3 times daily was equivalent to famvir 500 mg 3 times daily in a randomized study which excluded HZO.²⁹⁵ There was no difference in resolution of pain, rash healing, or post-herpetic neuralgia. This equivalence, despite the much longer intracellular half-life of the triphosphate form of penciclovir (the active moiety of famciclovir) compared to acyclovir triphosphate, has been attributed to the much greater inhibition of viral DNA polymerase by acyclovir triphosphate.^295,296

Valacyclovir is, like acyclovir, ineffective for the treatment of active CMV disease but has potential value as oral prophylaxis in solid organ transplant recipients. In CMV seronegative renal transplant recipients of seropositive donors, valacyclovir 2000 mg 4 times daily for 90 days reduced the incidence of CMV disease and the risk of acute graft rejection. There did seem to be an increased frequency of hallucinations and confusion.²⁸⁴ In patients with advanced HIV disease, oral chronic valacyclovir 2000 mg 4 times daily did reduce the risk of CMV disease compared with acyclovir, but with an increase in drug toxicity and mortality. Specifically, there was an increased risk of a frequently fatal thrombotic microangiopathy associated with this high dose of valacyclovir given for a median of 29 weeks.²⁸⁵

OPHTHALMIC USES

The ophthalmic indications for valacyclovir are essentially those for oral acyclovir. There are no published randomized controlled trials of valcyclovir for herpes simplex keratitis, but one would expect it to be at least as effective as oral acyclovir, with the advantage of more convenient dosing. Aqueous humor concentrations of acyclovir after valacyclovir administration are almost double those after oral acyclovir and are about 40% of plasma concentrations.²⁹⁷ The decision to use oral valacyclovir for ocular HSV infection should be based on the same considerations described in the section on acyclovir and should incorporate the conclusions of the HEDS. For acute herpetic epithelial keratitis or iritis, one would expect valacyclovir 1000 mg 2 or 3 times daily to be at least as effective and safe as acyclovir used 5 times daily, based on the results of trials of genital herpes.^290,291 Similarly, valacyclovir 1000 mg once daily should be at least as effective as twice-daily acyclovir for chronic suppressive therapy,^280,293 although in HIV-infected patients twice-daily valacyclovir might be preferred.²⁸⁰ In a mouse eye model of HSV-1, valacyclovir and famciclovir were equally effective in limiting the shedding of HSV-1 with equal rates of reactivation.²⁹⁶ In a rabbit eye model, valacyclovir prophylaxis reduced the rates of reactivation of HSV keratitis and ocular shedding of HSV-1 following excimer laser and laser-assisted in-situr keratomileusis (LASIK).^298,299 Controlled clinical trials are necessary to determine whether this would be effective or would warrant performing these procedures in patients with a history of herpetic keratitis.

Valacyclovir is at least as effective as oral acyclovir in the treatment of HZO. A large multi-centered randomized double-blind trial of herpes zoster in immunocompetent patients older than 50 years, in which 10% presented with HZO, compared valacyclovir 1000 mg 3 times daily with acyclovir 800 mg 5 times daily.²²² Overall, valacyclovir significantly accelerated the resolution of pain (by 1 to 2 weeks) and decreased the duration of post-herpetic neuralgia. However, in the HZO subgroup there was no significant difference between the drugs (possibly due to the small number of patients). This study also demonstrated no advantage of 14 days over 7 days of valacyclovir therapy. Colin and associates²²¹ compared valacyclovir 1000 mg 3 times daily with acyclovir 800 mg 5 times daily for 7 days in 110 immunocompetent patients over age 18 with HZO. All patients were treated within 72 hours of the rash. The drugs were equivalent in preventing ocular complications, healing skin lesions and effect on pain duration and severity and were equally well tolerated. At 2 months, ocular complications were present in 4% and 6%, respectively, of the patients reciving valacylovir and acyclovir . The most common adverse events were vomiting and edema of the eyelids or face, each occurring in 3% to 5% of patients. The authors concluded that the simpler dosing schedule of valacyclovir gave it an advantage in patient compliance.²²¹ A large observational study of immunocompetent patients with herpes zoster treated with 7 days of valacyclovir 1000 mg 3 times daily included HZO in 11% of patients.²⁸³ The rate of pain resolution was no different in patients with HZO, but abnormal sensations persisted longer. Overall, treatment was effective on cessation of pain even when started after 72 hours of rash onset, but this was not analyzed separately in the subgroup with HZO. There have been no comparative studies of valacyclovir and famciclovir for HZO, but a randomized controlled trial of non-ophthalmic zoster found these drugs to be comparable in efficacy and safety with no difference in the incidence of post-herpetic neuralgia (16% with each drug at 6 months).²⁹⁵ Valacyclovir, therefore, is a reasonable alternative to either oral acyclovir or famciclovir for the treatment of HZO in immunocompetent patients at a dosage of 1000 mg 3 times daily for 7 days. Treatment ideally should begin within 72 hours of the rash, but even later treatment may be effective.²⁸³ There is some evidence that it may shorten the duration (but not incidence) of post-herpetic neuralgia,^219,295 and it is relatively cost-effective when compared to the other agents.^295,300 However, as noted above, its beneficial effect in shortening the duration of zoster-associated pain in comparison to acyclovir has not been clearly demonstrated thus far in patients with HZO. The concomitant use of corticosteroids in elderly patients without contraindications has the same considerations as discussed in the section on acyclovir.^158b

There are no published controlled studies of valacyclovir treatment of HZO in immunocompromised or HIV-seropositive patients, and it is not approved for this indication. However, its pharmacokinetics and anecdotal experience suggest thatit would be an acceptable alternative to intravenous acyclovir in mildly immunocompromised patients without disseminated disease.^158b,161b Prolonged maintenance treatment may be necessary.

Treatment of the ARN syndrome is discussed in the section on acyclovir. Initial treatment should be with high-dose intravenous acyclovir. However, a reasonable alternative would be valacyclovir or oral acyclovir for 6 to 14 weeks following the completion of intravenous therapy. There is a report of the acute treatment of ARN with valacyclovir.²⁴³ A caveat is that all three patients received retinal laser prophylaxis against retinal detachment, which suggests that there was no severe vitritis and implies a relatively mild variant of ARN (see the section on acyclovir). It should also be noted that the dosage used (1000 mg three times daily) gives acyclovir levels comparable to 5 mg/kg intravenously. To achieve acyclovir levels comparable to the higher intravenous dosages typically used to treat ARN requires a valacyclovir dosage of 2000 mg four times daily.^275,276 The results of this study also suggest that these patients may have had a more mild variant of the ARN syndrome. Oral valacyclovir might be a reasonable alternative in a patient who refuses intravenous therapy.

MECHANISM OF ACTION, PHARMACOLOGY, AND TOXICITY

Penciclovir inhibits viral DNA synthesis. In infected cells penciclovir is preferentially phosphorylated to penciclovir triphosphate, its active form, which serves as a competitive inhibitor of viral DNA polymerase.³⁰¹ Unlike acyclovir, it is not an obligate chain terminator. Although penciclovir triphosphate is 100-fold less active in inhibiting viral DNA polymerase than acyclovir triphosphate, it can achieve much higher concentrations and more prolonged periods in infected cells. The prolonged intracellular half-life of penciclovir triphosphate (7 to 20 hours) is associated with a sustained antiviral effect on cell culture. This effect allows for infrequent dosing of the drug clinically. Because of its dependence on viral thymidine kinase for its initial phosphorylation, penciclovir is inactive against thymidine kinase-deficient strains of HSV or VZV but may be active against some TK-altered or polymerase mutants that are resistant to acyclovir and some foscarnet-resistant HSV-isolates.^302a

Famciclovir is a prodrug that is well absorbed orally and rapidly converted to penciclovir by deacetylation and oxidation of the purine. This occurs during and after absorption through the intestinal wall and in the liver.^302b The bioavailability of penciclovir averages 77% after oral administration of famciclovir. Little or no famciclovir is detected in the blood or urine The plasma half-life of penciclovir averages 2 to 3 hours, and approximately 70% is recovered unchanged in the urine.³⁰²

Oral famciclovir is well tolerated but may be associated with headache, nausea, and diarrhea, with a frequency similar to acyclovir.^303,304 In elderly patients, urticaria and rash, as well as confusion and hallucinations, also have been reported. Neutropenia and elevated liver enzyme levels occur in less than 5% of patients.

SYSTEMIC USES

Famciclovir has at least as much efficacy with equivalent safety as oral acyclovir in the treatment of HSV and herpes zoster infections but requires less frequent dosing.^{223,303,304,305} Oral famciclovir (250 mg 5 times daily for 5 to 10 days) is as effective as acyclovir in treatment of first episodes of genital HSV infection.³⁰⁵ In patients with recurrent genital HSV infection, patient-initiated famciclovir treatment reduces healing times and symptoms by approximately one day compared with placebo.^305a Suppressive therapy (250 mg twice daily) for up to 1 year is effective and well tolerated in persons with frequent recurrences.^305b In immunocompetent adults with herpes zoster treated within 72 hours, famciclovir (500 mg 3 times daily for 10 days) is as effective as acyclovir (800 mg 5 times a day)³⁰³ and superior to placebo in reducing both the acute manifestations and the duration (but not incidence) of postherpetic neuralgia, particularly in patients older than 50 years of age.^306,307 Famciclovir is also comparable to high dose acyclovir in the treatment of herpes zoster in immunocompromised patients.³⁰⁷

Penciclovir is available only as a topical cream for the treatment of herpes simplex labialis.³⁰⁸ There is no topical ophthalmic preparation.

OPHTHALMIC USES

In common with valacyclovir, the ophthalmic uses for famciclovir are those of oral acyclovir with the advantage of simpler dosing. There are no published trials of famciclovir as treatment for HSV keratitis. However, as with valacyclovir, one would expect it to be at least as effective as oral acyclovir. In a rabbit model, both topical penciclovir ointment and oral famciclovir reduced the severity of keratitis but were less effective than topical trifluridine.^309,310 Oral famciclovir did reduce the number of HSV-1 genomes in the trigeminal ganglion in this model, but it is not known if this translates into efficacy of prophylactic oral famciclovir for patients with recurrent herpes simplex keratitis.³¹⁰ In a mouse eye model, famciclovir and valacyclovir were equally effective in reducing the shedding and virulence of HSV-1, but neither prevented latency with equal rates of viral reactivation.²⁹⁶ As with valacyclovir, its effectiveness against herpes simplex keratitis can be extrapolated from studies of its use in genital and labial herpes infections as well as from anecdotal experience. Similarly, its use in this condition should undergo the same considerations as described for oral acyclovir, with its use limited to patients unsuitable for topical treatment plus those indications determined as appropriate in the HEDS. For acute epithelial keratitis 3 times–daily treatment should be at least as effective as 5 times–daily acyclovir.³¹¹ For chronic suppressive therapy, a twice-daily regimen seems more likely to be effective than a once–daily shedule.³¹²

Famciclovir is at least as effective as oral acyclovir in the treatment of HZO. Tyring and associates²²³ performed a multicenter randomized study comparing famciclovir 500 mg 3 times daily with oral acyclovir 800 mg 5 times daily for 7 days in 454 immunocompetent patients with HZO presenting within 72 hours of rash appearance and followed up for 6 months. The efficacy of the two drugs was similar, with no significant difference in the percentage of patients who experienced ocular manifestations (including “severe” manifestations) or visual acuity loss. The drugs were equally well tolerated. The most common side effects were nausea, vomiting, and headache, which occurred in 5% to 10% of patients. A similar study in non-ophthalmic zoster treated for 10 days demonstrated these drugs to be equivalent in accelerating cutaneous healing and loss of acute pain.³⁰³ Compared to placebo, famciclovir reduces the duration³⁰⁶ but not the incidence of post-herpetic neuralgia in patients with non-ophthalmic zoster. The benefit is greatest in those over 50 years of age and becomes apparent at 3 to 6 months of therapy.³⁰⁷ Famciclovir was also equivalent to valacyclovir in treating patients older than 50 years with nonophthalmic zoster. Postherpetic neuralgia was present at 6 months in 19% of patients receiving either drug.²⁹⁵ There has been no head-to-head comparison of these drugs in the treatment of HZO. Famciclovir, therefore, is effective in the treatment of HZO at a dosage of 500 mg 3 times daily for 7 days. Its benefit is greatest when started within 48 to 72 hours appearance of the rash, but patients may still benefit from later treatment, especially if new lesions are in evolution.

Famciclovir, like valacyclovir, might be considered for treatment of HZO in mildly immunocompromised patients, although not approved for this use.^158b,161b This is a convenient alternative to intravenous acyclovir but its use should be limited to patients without evidence of multidermatomal or disseminated disease. Famciclovir, also like valacyclovir, is a logical alternative to oral acyclovir for 6 to 14 weeks after the completion of intravenous high-dose acyclovir treatment of the ARN syndrome. There is a single case report of a patient with ARN who was successfully treated with 3 months of oral famciclovir after failing to respond to 2 weeks of intravenous acyclovir followed by oral acyclovir.²⁴⁴ It cannot be stated with certainty that famciclovir was responsible for the regression of active retinitis. One should be aware that HSV or VZV resistant to acyclovir usually is thymidine kinase–deficient and hence probably also resistant to famciclovir.³⁰¹

Famciclovir, therefore, has similar indications, efficacy, and safety as valacyclovir (or oral acyclovir). The choice of which drug to use will depend mainly on factors of convenience, availability, and cost.

MECHANISM OF ACTION, PHARMACOLOGY, AND TOXICITY

Ganciclovir is an acyclic nucleoside analog of deoxyguanosine that differs from acyclovir only by the addition of a terminal hydroxymethyl group (see Fig. 2). It is 10 to 25 times as active as acyclovir against CMV and at least as active against HSV-1 and HSV-2, VZV, and EBV.^313–317 As with acyclovir, the inhibition of viral replication is produced only by the triphosphate form of the drug. Although the mechanism of action is incompletely understood, ganciclovir triphosphate appears to function both as an inhibitor of and as a faulty substrate for CMV DNA polymerase. Host cellular polymerase is much less affected.^165,315 Ganciclovir triphosphate is incorporated into CMV DNA with a consequent reduction of DNA chain elongation. This effect is reversible, because virus production resumes when ganciclovir is removed from the media.^314,317 The drug is therefore virustatic. The initial phosphorylation reaction that produces ganciclovir monophosphate is the rate-limiting step for the synthesis of ganciclovir triphosphate. This is catalyzed by viral thymidine kinase in cells infected with herpes simplex.³¹⁸ CMV, however, does not produce thymidine kinase. Instead, ganciclovir is phosphorylated in CMV-infected cells by a phosphotransferase which is the CMV UL97 gene product.^318,319 Cellular kinases then convert it to the active triphosphate form.³¹⁵ It is the much more efficient phosphorylation of ganciclovir, compared with acyclovir, in CMV-infected cells that makes it a more effective agent against CMV.³²⁰ The intracellular phosphorylation of ganciclovir is relatively selective in that levels of ganciclovir triphosphate found within CMV-infected cells are ten times that within uninfected cells. However, bone marrow cells can be uniquely sensitive to ganciclovir,³¹⁵ which is why neutropenia is its major adverse effect.

Ganciclovir is poorly absorbed from the gastrointestinal tract. The oral bioavailability averages 6% to 9% when the drug is administered with food (and less without food).^321–324 At the approved oral dosage of 1000 mg 3 times daily, serum concentrations only approach the ED₅₀ of most clinical isolates^317,322 of CMV, explaining the inadequate efficacy of the oral drug for induction treatment of active CMV retinitis. The ED₅₀ for most clinical isolates of CMV is less than 5 μM, and this plasma level is easily reached with a 2.5- or 5-mg/kg intravenous dose.^325–328 Ganciclovir has a large volume of distribution and exhibits biexponential decay with a terminal elimination half-life of 3.60 hours.³²⁸ It penetrates the cerebrospinal fluid to achieve concentrations inhibitory to CMV.^325,326 Intraocular and subretinal fluid levels are above the ID₅₀ for most CMV strains and approach plasma levels.³²⁹ Vitreous levels following intravenous dosing are similar to those in plasma and average 1 μg/mL.³³⁰ Ganciclovir undergoes little or no metabolism. Its clearance is dependent on renal elimination and is correlated with creatinine clearance. Its half-life and plasma levels are increased in the presence of renal insufficiency, and, although not nephrotoxic, dosage reduction is necessary in the presence of renal dysfunction. Hemodialysis efficiently reduces ganciclovir plasma levels by about 50%, which suggests that the drug should be administered after dialysis.³²⁸ Ganciclovir implant and intravitreal administration are discussed later in this chapter.

In animal studies, ganciclovir is teratogenic and carcinogenic and causes azoospermia.³¹⁸ The most frequent adverse effects clinically have been hematologic, primarily neutropenia (40% of patients) and thrombocytopenia (20%). However, severe dose-limiting neutropenia (500/μL) and thrombocytopenia (25,000/μL) occur in about 20% and 10% of patients, respectively. These effects are usually reversible on discontinuation of ganciclovir, although irreversible neutropenia has been reported.³³¹ Less commonly reported adverse effects include fever, rash, phlebitis, nausea, hepatocellular dysfunction, and central nervous system symptoms, including confusion.^331–333 Symptoms of neurotoxicity may occur in the presence of renal impairment and are reversible with proper dosage adjustment.³³²

Although case reports suggest that the effect of ganciclovir in immunocompromised children is similar to that in adults,^334–336 additional studies are required to determine its efficacy, safety, and optimal dosage both in immunocompromised children and in infants with congenital CMV inclusion disease. Ganciclovir is not approved for pediatric use.

CMV resistance to ganciclovir is most commonly due to mutations in the UL97 gene encoding the viral phosphotransferase but also may be caused by DNA polymerase mutations (UL54 gene).³³⁷ Highly resistant variants have both UL97 and DNA polymerase mutations³³⁸ and are variably cross-resistant to cidofovir and foscarnet.^337,338

SYSTEMIC USES

Because of its toxicity, intravenous ganciclovir use has been limited to patients with AIDS and to other immunosuppressed patients with life- or sight-threatening CMV infections. Clinical improvement in 65% or more of patients has been found in uncontrolled studies of nonocular CMV syndromes in patients with AIDS, particularly in patients with CMV esophagitis, colitis, wasting syndrome, and possibly pneumonia.^331,335,336 Statistically significant clinical efficacy has not been established by randomized trials; however, one randomized trial demonstrated a short-term benefit of ganciclovir on CMV colitis.³³⁹ Variable responses have been described in central nervous system disease.^340,341 Many patients with AIDS and CMV syndromes relapse when ganciclovir use is discontinued. The benefit of maintaining these patients with nonocular disease on low-dose ganciclovir, as opposed to reinduction therapy for acute recurrences in the absence of immune reconstitution, has not been adequately determined. The introduction of highly active anti-retroviral therapy (HAART) may improve immune function and negate this issue (discussed later).

CMV infection is the single most frequent infectious complication in transplant recipients. Prophylactic ganciclovir treatment benefits seropositive heart transplant recipients³⁴² and bone marrow transplant recipients who are excreting CMV.^343,344 In bone marrow transplant recipients with CMV pneumonia, virologic responses without a reduction in mortality have been observed with intravenous ganciclovir treatment alone³⁴⁵ or together with corticosteroid.³⁴⁶ The combination of ganciclovir and anti-CMV immune globulin in these patients has been associated with an improved survival compared with that in historical controls.^347–349 Uncontrolled studies have also suggested that renal or heart transplant recipients and other immunosuppressed patients with CMV pneumonia or other CMV syndromes may have a good response to ganciclovir treatment.^350–352

In a meta-analysis of 13 randomized placebo-controlled trials involving 1138 patients, Couchoud and associates³⁵³ assessed the efficacy of antiviral agents (acyclovir and ganciclovir) in solid-organ transplant recipients for the prevention of CMV infection and disease. They demonstrated a clinically significant beneficial effect of these agents when used for prophylaxis of CMV infection and disease. It was estimated that the administration of prophylactic treatment to 100 patients would avoid 18 incidences of CMV disease and 19 incidences of CMV infection.

However, controversy exists concerning which antiviral agent is most appropriate. A meta-analysis of all high-quality randomized trials published before October 1999 and comparing ganciclovir versus acyclovir versus placebo concluded that ganciclovir was more effective than acyclovir for prophylaxis against CMV disease.³⁵⁴

Koetz and colleagues^354a compared preemptive CMV pp65 antigen–guided intravenous ganciclovir therapy and placebo in solid-organ transplant recipients seropositive for this CMV antigen but without clinical CMV disease. They found that preemptive therapy benefited high-risk patients when initiated at the first CMV pp65 antigen–positive test result. The occurrence and predictors of recurrent CMV infection in solid-organ transplant patients despite preemptive treatment was recently studied by Muheim and co-workers,³⁵⁵ who found that CMV infection occurred in 63 out of 101 patients, 31 of whom experienced recurrent infection ranging from 1 to 9 episodes. These authors concluded that use of CMV prophylaxis was important in donor-positive and recipient-negative (D⁺/R^-) recipients.³⁵⁵

Oral ganciclovir at a dosage of 1 g three times a day for 98 days or a combination of IV ganciclovir followed by high-dose oral acyclovir markedly reduces the risk of CMV disease in liver transplant recipients, including the high-risk group comprising seronegative recipients of seropositive donors.^355a A similar 12-week regimen was also effective in renal transplant recipients.^355b Oral ganciclovir may be superior to oral acyclovir following IV ganciclovir.^355c For primary prophylaxis, oral ganciclovir (1 g every 8 hours) decreases the incidence of CMV disease in HIV-infected persons with CD4 counts less than 100 cells/mL, as discussed later.

OPHTHALMIC USES

Ganciclovir was the first drug with FDA-approved labeling for the treatment of CMV retinitis in immunocompromised persons. Despite the disadvantages of intravenous administration and potential bone marrow toxicity, it represented a major advance in the treatment of what had been an almost uniformly progressive disorder leading to blindness within weeks to months in patients with AIDS.³⁵⁶ CMV retinitis occurs only in immunosuppressed persons.⁹⁰ Most studies in the pre-HAART era estimated a 20%- to 40%-prevalence of CMV retinitis in patients with AIDS,^356–359 with 2% having CMV retinitis as the first manifestation of AIDS.³⁶⁰ About 25% of patients with CD4 counts below 100 cells/mL not being treated with HAART will develop CMV retinitis within 1 year,³⁶¹ with most of those having CD4 counts below 50 cells/mL.^358,361

The recommended dosage is 5 mg/kg intravenously every 12 hours for 14 to 21 days of initial or induction treatment, followed by a maintenance dosage of 5 mg/kg once daily every day. The dosage must be reduced in the presence of renal dysfunction.

Induction Therapy

Open-label uncontrolled trials of ganciclovir administered in a compassionate-use protocol demonstrated anatomic stabilization or improvement of CMV retinitis in at least 80% of patients with the use of an induction dosage of either 2.5 mg/kg every 8 hours or 5 mg/kg every 12 hours for 10 to 21 days.^{325,331,359,362–367} There is no apparent difference between these two regimens in either efficacy or toxicity.³³¹ Although these studies indicated a beneficial effect of ganciclovir, they were neither randomized nor controlled and did not have standardized, objective criteria for assessing disease outcome. Holland and associates,³⁶⁸ in a controlled retrospective study, used a strict standardized assessment of retinal photographs to determine whether induction therapy with ganciclovir stops or delays the progression of CMV retinitis. Disease progression occurred in 94% of untreated patients but in only 43% of treated patients. The proportion of treated patients with progression in this study was higher than in previous studies because of the strict photographic criteria used and because enlarged lesions were considered to have progressed even if there was decreased activity of the retinitis. Using similar criteria, a small randomized controlled trial found that intravenous ganciclovir 5 mg/kg twice daily for 14 days followed by 5 mg/kg once daily significantly prolonged the time to progression to 50 days compared to 14 days with deferred treatment.^368a

Visual acuity is not normally a useful parameter for assessing the response to treatment because it will not improve unless there is a decrease in any coexisting macular edema or vitritis. CMV-infected retinitis results in a permanent scotoma. The final vision depends mainly on the anatomic location of the infection. In one long-term study, 18% of patients had a final vision of 20/200 or worse, but the vision of nearly 75% was 20/40 or better.³⁶⁹ In a randomized study comparing ganciclovir with foscarnet, vision in about 90% of patients in each group after 6 months was 20/40 or better in at least one eye; however, 23% lost 6 or more lines of vision in one eye.³⁷⁰

Retinitis regression usually begins within 1 to 2 weeks. It is indicated by decreased opacification of lesion margins, lack of further lesion enlargement, and resolution of any vasculitis.^{362,363,365,366,368,370} However, there may be some lesion enlargement in the first 2 weeks even with successful therapy.³⁷¹ Healing is usually complete in 3 or 4 weeks.^{359,365,368,371}

Ganciclovir reduces and delays but does not eliminate the possibility of second eye involvement in unilaterally affected patients. Second eye involvement without systemic treatment occurs in 40% to 60% of patients, but only in about 15% to 20% of patients receiving systemic ganciclovir.^369,370

Maintenance Therapy

The virustatic action of ganciclovir on CMV is demonstrated by the recurrence of CMV retinitis (usually at the margins of preexisting healed lesions) following successful induction therapy in almost all patients with AIDS within 2 to 6 weeks of its discontinuation.^{331,361–364,366,367} Histopathologic, electron-microscopic, and immunofluorescent studies of eyes treated with ganciclovir have revealed persistent viral particles in the retina.^372–374 Ganciclovir, through reversible inhibition of CMV DNA polymerase, appears to function by limiting viral DNA synthesis and the subsequent packaging of viral DNA into infectious units, but it does not eliminate all viruses or prevent viral protein synthesis.^{314,316,317,372,373} On the removal of ganciclovir, DNA synthesis resumes and infectious virus reappears.^314,317

Most studies of maintenance intravenous ganciclovir therapy of CMV retinitis have utilized a dosage of 5 mg/kg once-daily for 7 days a week. Lower or less frequent doses are generally ineffective.^331,364,367 Although available evidence indicates that ganciclovir is beneficial in delaying the recurrence of CMV retinitis, there have been no published, large randomized controlled prospective trials. Data from the manufacturer demonstrates that the median time to relapse is delayed to 105 days in those receiving high-dose (25 to 35 mg/kg/week maintenance therapy compared with 47 days in those receiving low-dose (10 to 15 mg/kg/week or no maintenance therapy.³³¹ In a small randomized study, Jacobson and colleagues³⁷⁵ found the that median time to retinitis progression following 10 days of ganciclovir induction increased from 16 to 42 days with maintenance ganciclovir therapy.

In the absence of immune recovery (e.g., with HAART therapy), most patients will have progression of their disease in 2 to 4 months despite the use of daily intravenous maintenance ganciclovir. The studies of Ocular Complications of AIDS (SOCA) research group in a randomized study utilizing strict photographic criteria to compare ganciclovir with foscarnet in the pre-HAART era determined the drugs to be equally effective. The median time to progression with ganciclovir was 47 days, and 85% of patients had progressed within 4 months.³⁷⁰ Recurrence or progression of disease is likely inevitable unless there is reconstitution of the immune system. Jacobson and colleagues³⁷⁵ have pointed out that with once-daily intravenous 5 mg/kg ganciclovir, serum levels are below the ED₅₀ for CMV for about half the day. Average intravitreal levels after a maintenance intravenous ganciclovir dose of 5 mg/kg are only 1 μg/mL.^370,375a About a third of recurrences may have the subtle pattern of a “smoldering” retinitis,^363,369 often detectable only by comparing serial fundus photographs. It appears that most initial recurrences are due to inadequate intraocular levels of ganciclovir for a particular patient's immune status rather than ganciclovir resistance, because the preponderance of recurrences respond well to reinduction therapy.^{362,365,369,370} However, the time to progression of disease shortens with each reinduction,³⁷⁰ indicating that intraocular drug levels are likely inadequate to completely suppress viral replication, allowing the development of resistance. Ganciclovir-resistant strains of CMV have been reported in 7.6% of patients with CMV retinitis treated for 3 months or more³⁷⁶ and have been isolated from the blood or urine in 27% of patients by 9 months of therapy.³⁷⁷ The detection of ganciclovir-resistant CMV increases the risk of both retinitis progression and contralateral eye involvement.³⁷⁸

Retinal detachments occur despite successful long-term maintenance ganciclovir treatment of CMV retinitis with a risk of up to 37.9% at 1 year. This risk is related to the extent of retinal involvement as well as the degree of immunosuppression³⁷⁹ and is reduced by the use of HAART therapy.³⁸⁰

The major toxicity of ganciclovir in studies of maintenance ganciclovir therapy of CMV retinitis has been myelosuppression, resulting in neutropenia or, less commonly, thrombocytopenia.^{359,362–365} Dose-limiting neutropenia occurs in up to 34% of patients.^{359,362,365,381} This problem can be obviated by the use of filgrastim (granulocyte colony–stimulating factor), which also seems to have a beneficial effect on survival.³⁸²

For patients with one or more recurrences, the CMV Retinitis Retreatment Trial (discussed in the section on foscarnet) demonstrated that the combination of intravenous ganciclovir and intravenous foscarnet as maintenance therapy produced longer median remissions than either drug alone. This was, however, at the cost of a negative impact on quality of life.^382a

Oral Ganciclovir

The use of intravenous ganciclovir as chronic maintenance therapy (especially in the pre-HAART era or currently in patients unresponsive or intolerant of HAART therapy) requires long-term intravenous access via an indwelling catheter. This has an adverse effect on quality of life as well as being an added expense, compounded by the risk of catheter-related sepsis.³⁸³ Although less effective than intravenous ganciclovir, oral ganciclovir avoids these catheter-associated problems and has been approved for maintenance (but not induction) therapy of peripheral CMV retinitis at a dosage of 11,000 mg three times daily.

Two small randomized trials of oral ganciclovir 500 mg 6 times daily versus intravenous ganciclovir 5 mg/kg once daily, following induction and stabilization of CMV retinitis with intravenous ganciclovir, gave similar results.^384,385 In both the U.S./Canadian³⁸⁴ and European/Australian³⁸⁵ trials, there was no statistically significant difference in the times to progression on the basis of masked fundus photographs, although there was a wide difference in the medians (29 days oral vs. 49 days intravenous, and 41 days oral vs. 60 days intravenous, respectively), and in the latter trial the mean time to progression was significantly shorter with oral therapy in those patients taking concomitant antiretrovirals. Furthermore, there was a statistically significantly more rapid mean time to progression with oral therapy in both studies, on the basis of funduscopy by ophthalmologists, as well as a higher rate of new lesions being found by clinicians in patients on oral therapy.³⁸⁴ These differences most likely reflect the fact that a larger area of peripheral retina can be visualized with indirect ophthalmoscopy than with fundus photography.³⁸⁶ This indicates that oral ganciclovir is of only modest benefit in retarding the progression of CMV retinitis when used for maintenance, consistent with its poor oral absorption.³²² Therefore, it should not be substituted for intravenous ganciclovir as sole maintenance therapy of lesions threatening the optic nerve or fovea, and it is inappropriate for induction therapy.

There is evidence that higher doses (4.5 g/day and 6 g/day) are more effective than the FDA-approved dosage of 3 g/day.³²³ Also, oral ganciclovir in a dosage of 1.5 g three times daily given in conjunction with a ganciclovir implant, when compared to oral placebo with a ganciclovir implant, reduced the risk of new CMV disease (including contralateral CMV retinitis), extended the therapeutic effect of the implant, and lowered the risk of development of Kaposi's sarcoma (which is associated with HHV-8).³⁸⁷ However, the newly available and much better absorbed oral drug valganciclovir will undoubtedly supplant oral ganciclovir (and probably intravenous ganciclovir) for these and other uses.

Oral ganciclovir has received FDA approval for prophylaxis of CMV disease in HIV-infected patients with CD4 lymphocyte counts less than 100/mL at a dosage of 1000 mg three times daily. Roche study #1654 was a double-blind placebo-controlled trial which showed that oral ganciclovir in the above dosage was beneficial in HIV-infected patients with CD4 counts less than 100/mL.³⁸⁴ Ophthalmologic examinations were performed and viral cultures obtained at entry and every 2 months thereafter. The rate of development of CMV disease (primarily CMV retinitis) at 1 year was 26% in placebo recipients compared to 14% in patients receiving ganciclovir (p < 0.001). Oral ganciclovir decreased the 1-year risk of CMV retinitis from 24% to 12%. This translates into a significant 50% reduction in risk for developing CMV and organ disease. There was no statistically significant survival benefit.

A conflicting result was reported by the Community Programs for Clinical Research on AIDS (CPCRA).³⁸⁸ This group found no difference between placebo and oral ganciclovir at the same dosage in preventing CMV disease in HIV-infected patients who also had CD4 counts less than 100 cells/mL. The differing results are perhaps explained by differences in study design, drug exposure, and study populations.³⁸⁹ In the CPCRA study, neither baseline nor follow-up ophthalmologic examinations were required in the absence of visual symptoms. Therefore, asymptomatic retinitis would not be detected, and some patients may have already had CMV retinitis on entry. The #1654 patients received blinded treatment for a longer duration because, when the results of this study were released, patients in the placebo arm of the CPCRA study were offered the option of switching to oral ganciclovir. Finally, the #1654 patients were as a group more immunosuppressed with lower median CD4 counts, and there were more patients with CD4 counts less than 50 cells/mL. The results of study #1654 are also supported by the study mentioned above in which oral ganciclovir 4.5 g/day given to patients with a ganciclovir implant lowered the risk of additional end-organ disease.³⁸⁷ It is of interest that the benefit of prophylactic oral acyclovir was greatest in those patients who were CMV polmerase chain reaction (PCR)–negative or who had low PCR levels.³⁹⁰ It provided no benefit to those with CMV PCR levels of more than 50,000 copies/mL. This suggests that the benefit was limited to true prophylaxis and that oral acyclovir provides serum levels too low for preemptive therapy in those most likely to develop CMV retinitis.

It does appear, therefore, that oral acyclovir is of some limited benefit for prophylaxis. It is, however, not recommended routinely for primary CMV prophylaxis because of suboptimal reduction in disease, lack of a survival benefit, high pill burden, and high cost.³⁹¹ Also, in the HAART era, the degree of risk for CMV retinitis may be reduced even in some patients with low CD4 counts.

Ganciclovir Implant

The difficulties of long-term intravenous therapy with ganciclovir and/or foscarnet via an indwelling catheter (as noted previously), as well as the toxicities and limited efficacies of these drugs (especially in the pre-HAART era), prompted the development of the intraocular ganciclovir implant. This is a sustained-release drug delivery device that contains a tablet of 4.5 mg ganciclovir coated with polyvinyl alcohol, which is permeable to ganciclovir, and in turn partially coated with ethylene vinyl acetate, which is impermeable to ganciclovir.^{392,392a,392b} It is placed in the vitreous through a 5- to 6-mm pars plana incision and sutured to the sclera. It is usually placed inferotemporally to maximize the chance for it to exist in an inferior aqueous humor meniscus, in case the patient should develop a retinal detachment repaired with silicone oil.^393–395 It releases the drug at a rate of about 1 μg/mL,^392b four times higher than the rate achieved with maintenance intravenous ganciclovir.^330,375a This produces a longer therapeutic effect than is possible with systemic therapy^392a,392b while avoiding systemic toxicity. However, the lack of systemic therapy increases the risk of CMV disease in other organs as well as in the contralateral eye.^{273,375a,392b} It should therefore be used in conjunction with systemic therapy, preferably oral valganciclovir or oral ganciclovir.

In a randomized clinical trial, the median time to progression of newly diagnosed CMV retinitis was 221 days with the ganciclovir implant (essentially until it was depleted of drug), compared to 71 days with intravenous ganciclovir. As expected, the patients receiving the implant were more likely to develop fellow eye involvement than those receiving intravenous gangciclovir (40% vs. 16%) as well as extraocular CMV disease (10.3% vs. 0%), while 31% had biopsy-proven visceral disease.^392b

In an attempt to address the issues of systemic and contralateral ocular disease, a randomized controlled study of AIDS patients with unilateral CMV retinitis was performed, as discussed in the section on oral ganciclovir.³⁸⁷ Patients were assigned to receive the ganciclovir implant plus oral ganciclovir (4.5 g/day), the implant plus oral placebo, or intravenous ganciclovir alone. The risk of new CMV disease was significantly reduced in both the oral ganciclovir plus implant (24.3%), and intravenous ganciclovir (19.6%) groups compared to the placebo plus implant group (44.3%). However, in those patients using protease inhibitors (a component of HAART), the incidence of new CMV disease was low with no difference among the treatment groups. Oral ganciclovir further extended the benefit of the implant on progression of retinitis compared to intravenous ganciclovir alone. As noted previously, both oral and intravenous ganciclovir reduced the risk of developing Kaposi's syndrome.

The higher intraocular drug levels achieved with the ganciclovir implant may also allow control of CMV retinitis in some patients poorly responsive to intravenous ganciclovir.^396,397 However, the implant may be less effective in recurrent CMV retinitis than when used for initial treatment,^398,399 especially with 6 months or more of intravenous therapy.³⁹⁸ Once the implant is depleted of drug, unless the patient has had a response to HAART therapy, retinitis may be reactivated, necessitating a new implant either in exchange for the depleted one or inserted into a new site. Planned replacement might be considered in patients who have no hope of immunologic improvement with vision-threatening (Zone 1) disease. Otherwise the patient may be observed monthly beginning around the time of anticipated depletion of the implant.³⁹³ HAART therapy may greatly prolong the time until recurrent disease develops.⁴⁰⁰

The most common complication associated with the ganciclovir implant is a transient decrease in vision due to temporary astigmatism, which resolves in 4 weeks.^392a,392b Some of the more common complications include retinal detachment, endophthalmitis, vitreous hemorrhage, cystoid macular edema, and cataract.^{387,392a,392b,393,401,402} Other complications include hypotony, extrusion of the implant, and anterior chamber or suprachoroidal placement.^{393,402–404} There seems to be an early increased risk of retinal detachment compared to intravenous therapy, but this is balanced by a decreased long-term risk as a result of improved control of retinitis. Long-term, there is no statistically significant difference.^387,393,405 Endophthalmitis has a reported prevalence of 0.3% to 2.4%,^{387,392a,393,401} being 0.3% to 0.5% in the largest studies.³⁹³

The availability of HAART has a bearing on the use of the ganciclovir implant. It is probably best reserved for patients with vision-threatening or recurrent disease who are intolerant of, unresponsive to, or unlikely to respond to or non-compliant with HAART or with systemic anti-CMV agents. In the only comparative clinical trial in the HAART era, the ganciclovir implant plus oral ganciclovir 1000 mg 3 times daily was equal in efficacy to intravenous cidofovir given every 2 weeks and was better tolerated.⁴⁰⁶ There was more visual field loss in the ganciclovir group, probably due to the implant itself blocking part of the visual field because there was no increased rate of retinal involvement. Uveitis and nephrotoxicity were more common with cidofovir. Retinitis progression was very low in both groups (0.57 and 0.76 per person-year, respectively), probably as a result of HAART.

Effects on Survival

An important consideration is whether ganciclovir treatment of CMV retinitis can affect survival in AIDS patients, in whom there are usually simultaneous tissue-invasive CMV infections in other organs.⁴⁰⁷ In 1984, before the development of anti-HIV therapy, the median survival after the diagnosis of CMV retinitis in patients with AIDS not treated with ganciclovir was only 120 days.⁴⁰⁸ Ganciclovir treatment promoted body cell mass repletion in the pre-HAART area in patients with AIDS with serious CMV infections,³³⁸ which was partly attributed to an improved sense of well-being with improved appetite.^338,362,365 In patients with retinitis, this might reflect an effect of ganciclovir on early occult CMV infections elsewhere in the body.^362,365 It has also been theorized that ganciclovir could improve survival by limiting a possible transactivating effect of CMV on HIV.⁴⁰⁹ Holland and associates,⁴¹⁰ in a large, nonrandomized, retrospective study pre-dating effective anti-retroviral therapy, found that patients treated with ganciclovir had a statistically significant longer survival after the diagnosis of CMV retinitis (median, 7 months) than untreated patients (median, 2 months). This suggests, but does not prove, that ganciclovir improved survival. A multicenter randomized controlled study of CMV retinitis treated with either intravenous ganciclovir or foscarnet was performed by theSOCA group as the first anti-retroviral drugs were just beginning to be used. It determined that, while the two drugs were equally effective in the treatment of CMV retinitis, there was survival benefit to patients with AIDS using foscarnet (except in those with decreased renal function, who live longer with ganciclovir therapy).⁴¹⁵ This was ascribed to a mild anti-retroviral effect of foscarnet. Interestingly, both drugs had a suppressive effect on circulating HIV p24 antigen, which was predictive of improved survival.⁴¹⁶ This supports the notion that inhibition of CMV replication may also have a beneficial effect on limiting HIV replication. This survival advantage of foscarnet was not present in a later study comparing combination therapy with individual therapy, probably because of increased antiretroviral drug usage.^382a In the HAART era, this is not an important consideration.

Alternative Strategies

In patients with relapsed retinitis despite maintenance therapy (clinical resistance), there is evidence that combination therapy is superior to reinduction and higher dose maintenance with a single drug. The SOCA CMV Retinitis Retreatment Trial randomly assigned patients with relapsed CMV retinitis to standard treatment with intravenous ganciclovir or foscarnet, or to combination therapy with intravenous ganciclovir 5 mg/kg plus foscarnet 90 mg/kg daily.^382a The combination produced a longer median remission (4.3 months) than either ganciclovir (2 months) or foscarnet (1.3 months) alone. There was no significant mortality difference between any of the groups. Unfortunately, this study (performed pre-HAART) showed that the combination of intravenous drugs had a greater negative effect on quality of life measures. Currently, this negative impact could be ameliorated by using oral valganciclovir or the ganciclovir implant in combination with intravenous foscarnet.

In patients who are unwilling ^or unable to undergo or unresponsive to systemic therapy or implant in the presence of progressive vision-threatening retinitis, an alternative regimen to consider is intravitreal injection of ganciclovir. This modality is not an FDA-labeled use of the drug. Henry and associates⁴¹³ showed that an intravitreal dosage of 200 μg in 0.1-mL sterile water gives intravitreal ganciclovir levels above the ED₅₀ of CMV for 62 hours, with a half-life of 13.3 hours. Induction theoretically requires twice-weekly injections for 2 to 3 weeks. This dosage appears to be nontoxic to the retina.^413–418 Repeated weekly injections in rabbit eyes have demonstrated electroretinographic and electron-micrographic (but not clinical) evidence of retinal toxicity.³⁴⁶ From 78% to 100% of patients have responded to twice-weekly 200-μg or 400-μg injections of intravitreal ganciclovir.^{343,347,414,416,417,419,420} Maintenance treatment is given as a once-weekly injection.⁴¹⁸ Recurrences are about as likely as with intravenous treatment.^{414,417,418,420} Most injections given today, however, are 2 mg in 0.05 to 0.1 mL, which anecdotally has been more effective without increased toxicity.^421,422 This dosage provides mean vitreous ganciclovir concentrations of 144 μg/mL at 24 hours and 23 μg/mL at 72 hours with a mean calculated half-life of 18.3 hours and suggests that elimination takes 7 days.⁴²³ This provides a rationale for once-weekly maintenance therapy. Young and associates⁴²² reported a series of 42 patients (74 eyes) who received intravitreal 2-mg injections twice weekly for 3 weeks and then once weekly. Seven percent of eyes had a relapse in a median of 42 weeks based on clinical examinations. There were 3 cases of endophthalmitis. Five rabbit eyes which they treated with 1 mg weekly for 4 weeks showed no evidence of toxicity. Occasionally, patients may require injections with both intravitreal ganciclovir and foscarnet^424,425 and one patient received repeated injections of 3 mg ganciclovir with no toxicity.⁴²⁵ However, inadvertent injection of 40 mg intravitreal ganciclovir did result in severe retinal toxicity.⁴²⁶ Bacterial endophthalmitis, retinal detachments, and vitreous hemorrhage^{414–416,418,422} are potentially serious complications of this therapy. Although intravitreal ganciclovir avoids systemic toxicity, it also has no systemic effect on CMV. It does not protect the fellow eye from CMV infection, and extraocular CMV disease can occur.^418,420,422

Because ganciclovir is effective against herpesviruses other than CMV, there is interest in its use for herpetic keratitis. A topical ganciclovir ophthalmic gel, used in clinical trials in Europe and Africa, was equivalent to topical acyclovir ointment for the treatment of herpes simplex dendritic keratitis.^427,428

MECHANISM OF ACTION, PHARMACOLOGY, AND TOXICITY

Valganciclovir is a mono-valyl ester prodrug which, after oral administration, is well absorbed and rapidly hydrolyzed to ganciclovir (the active moiety) by intracellular esterases in the intestine and liver.⁴²⁹ Its pharmacodynamic properties, antiviral activity, and toxicity are essentially those of ganciclovir. The absolute bioavailability of ganciclovir from valganciclovir is 60 percent (10-fold higher than from oral ganciclovir)^430,431 and an oral dose of 900 mg valganciclovir (two 450-mg tablets) results in ganciclovir exposure (AUC_24h) comparable to 5 mg/kg of intravenous ganciclovir. The maximal concentration of ganciclovir achieved with oral valganciclovir is 59% to 67% of that achieved with intravenous ganciclovir.⁴³¹ Less than 2% of an absorbed dose appears as valganciclovir in plasma.⁴²⁹ Because administration of valganciclovir with food increases systemic exposure to ganciclovir,⁴³² it is advised that it be taken with meals. As with ganciclovir, dosage should be adjusted in the presence of renal dysfunction.^429,437 Patients with creatinine clearances below 10 mL/minute or receiving hemodialysis should instead receive intravenous ganciclovir because they require less than 450 mg (one tablet)/dose.^433,434

In the only published comparative study of valganciclovir with intravenous ganciclovir, the tolerability profiles were similar for induction. There was a higher incidence of diarrhea with valganciclovir (19% versus 10% for IV ganciclovir) but, as expected, more intravenous catheter–related events with ganciclovir (9%) than with valganciclovir (4%, in patients receiving other intravenous therapies).⁴³¹ Other adverse effects were essentially the same, including neutropenia (13% with ganciclovir and 14% with valganciclovir). A safety study of long-term oral valganciclovir maintenance also revealed that clinical toxicity and laboratory abnormalities were similar to those reported for intravenous ganciclovir. The most common adverse events were diarrhea (35%), nausea (23%), fever (18%), neutropenia (10%) and anemia (12%).⁴³⁵ There have been no cases reported of thrombotic microangiopathy/hemolytic-uremic syndrome.^431,435

SYSTEMIC USES

Because oral valganciclovir provides much higher serum levels of ganciclovir than does oral ganciclovir, it will likely replace oral ganciclovir for all systemic indications. Ongoing trials are investigating its use for the prevention of CMV disease following solid organ, bone marrow, and stem cell transplants.^435a

OPHTHALMIC USES

Oral valganciclovir is comparable to intravenous ganciclovir for induction and maintenance treatment of CMV retinitis in AIDS.^431,435 Although this is currently its only approved indication, it will likely replace both intravenous and oral ganciclovir for most of their current ophthalmic uses. A randomized controlled trial compared oral valganciclovir 900 mg twice daily for 3 weeks followed by 900 mg once daily for 1 week with intravenous ganciclovir 5 mg/kg twice daily for 3 weeks followed by 5 mg/kg once daily for 1 week for the treatment of newly diagnosed AIDS-related CMV retinitis.⁴³¹ At the end of 4 weeks, both groups were maintained on oral valganciclovir 900 mg once daily. By week 4, progression of retinitis as determined by fundus photographs occurred in 10% of patients in each group, indicating the equivalence of the two drugs for induction treatment. The median times to progression during maintenance therapy were similar (160 days in those initially assigned to valganciclovir and 125 days in those initially assigned to intravenous ganciclovir), as might be expected, because both groups were maintained on valganciclovir. The prolonged times to progression compared to previous trials of intravenous therapy are almost certainly due to the use of highly active antiretroviral therapy (HAART) by patients in this study. Contralateral CMV retinitis occurred in 15% of those with initially unilateral retinitis over the course of the study, which is similar to prior studies of intravenous ganciclovir maintenance. Adverse event rates, particularly neutropenia, were similar, the main difference being more diarrhea with oral valganciclovir and more catheter-related complications with intravenous ganciclovir.

A safety study of oral valganciclovir maintenance treatment of CMV retinitis in 212 AIDS patients confirmed these findings. Progression occurred in 17% of patients over a median duration of treatment of 372 days.⁴³⁵ A median time to progression could not be calculated, but it was estimated that it would have taken 456 days for 25% of patients to progress. Those who progressed were more likely to have a lower CD4 count. Again, these prolonged times to recurrence may be greatly attributed to HAART therapy. Six percent of patients with unilateral retinitis developed contralateral disease, and only 1% developed extraocular CMV disease. Valganciclovir does not seem to increase the rate of emergence of ganciclovir-resistant CMV.⁴³⁶

In summary, oral valganciclovir should be considered under most circumstances to be the drug of choice for treatment of CMV retinitis at an induction dosage of 900 mg twice daily for 3 weeks followed by 900 mg once daily for chronic maintenance.

MECHANISM OF ACTION, PHARMACOLOGY, AND TOXICITY

Foscarnet is a pyrophosphate analog of phosphonoacetic acid (see Fig. 2) with in vitro activity against all known human herpes viruses (including CMV, EBV, and HHV-8), hepatitis B virus (HBV), and some retroviruses, including HIV.^439–443 Its antiviral activity is exerted through a selective, reversible, noncompetitive inhibition of virus-specific DNA polymerases and reverse transcriptases (RNA polymerases) at concentrations that do not affect cellular DNA polymerases.⁴⁴⁴ Because foscarnet directly affects the pyrophosphate binding site of DNA polymerase, it does not require phosphorylation to be active.⁴⁴¹ It has, therefore, potential utility in the treatment of thymidine kinase–deficient acyclovir-resistant HSV and VZV infections^{265,269,270,274,438} and ganciclovir-resistent CMV infections.^445,446 A further advantage over ganciclovir is foscarnet's intrinsic anti-HIV effect.^440,442,447 This could make foscarnet a desirable alternative for the treatment of CMV infections in patients with AIDS. Most strains of CMV are inhibited by 100 to 300 μM of foscarnet,^439,448 98% of HIV replication is inhibited by 132 μM,⁴⁴² and the ID₅₀ for acyclovir-resistant HSV has been 100 μM or less.⁶¹ Foscarnet is not metabolized in the body and is rapidly eliminated in the urine through renal tubular secretion and glomerular filtation.⁴⁴¹ Thus, the dosage must be adjusted in patients with impaired renal function. Plasma concentrations during and after intravenous infusion are described by a three-compartment model. The disposition of foscarnet is triphasic with mean half-lives of 0.45, 3.3, and 18 hours.⁴⁴⁹ Foscarnet sequesters in bone with a very long terminal half-life, possibly lasting months.^441,450 Up to 20% of intravenously administered drug in patients with AIDS may be deposited in bone 7 days after infusion.^441,450 Foscarnet penetrates into the cerebrospinal fluid of HIV-infected patients in concentrations varying from 13% to 68% of the plasma concentration.⁴⁵⁰ Vitreous levels average 1.4 times that in plasma.³³⁰ In rabbits, retina levels exceed those in the vitreous.⁴⁵¹

Foscarnet is administered intravenously. Early studies administered a bolus of 20 mg/kg over 30 minutes followed by a continuous infusion of 230 mg/kg/24 hours for 2 to 3 weeks. A preferable regimen is 60 mg/kg over 1 to 2 hours three times daily. In HIV-infected patients, the plasma half-life of foscarnet after a 2-hour intravenous dosage of 60 mg/kg is about 4 hours, with virtually no drug detectable after 23 hours.⁴⁵² This yields peak plasma levels above the ID₅₀ for most CMV strains.^441,448,453 There are no major differences in the pharmacokinetic profiles of foscarnet administered as 90 mg/kg twice daily or 60 mg/kg 3 times daily; the former regimen is more convenient for induction therapy of CMV retinitis.⁴³⁹

Oral absorption of foscarnet is very poor, resulting in ineffective serum drug levels and frequent gastrointestinal side effects.^449,454 Oral bioavailability is less than 10%.⁴⁵⁴

As with ganciclovir, foscarnet is administered in a biphasic manner. An initial 2- to 3-week induction period utilizes an intermittent intravenous infusion of 60 mg/kg over 1 to 2 hours given every 8 hours, or 90 mg/kg given every 12 hours. This is followed by a maintenance regimen of 90 to 120 mg/kg once daily given over 2 hours. Foscarnet must be administered through an infusion pump.⁴³⁹

Azotemia is the most common serious adverse effect. The incidence of renal impairment has been reported to be as high as 45% in patients with AIDS.^{447,448,455,456} However, the intermittent, rather than constant, intravenous infusion method of induction reduces the incidence of nephrotoxicity to about 25%.^437,439,457 In most patients, the elevations in serum creatinine levels have been reversible (usually within 2 to 4 weeks) following dosage reduction or cessation of medication.^439,457 Because foscarnet is both renally excreted and nephrotoxic, frequent monitoring of renal function with dosage adjustment based on the creatinine clearance is critical. It is recommended that this be done three times a week during induction and weekly during maintenance therapy.⁴⁵² Hydration with 1 liter of normal saline or 5% dextrose solution intravenously may decrease the incidence of renal toxicity, especially during maintenance therapy.⁴⁵⁵ Foscarnet has been used successfully in a hemodialysis-dependent patient with careful monitoring of peak plasma levels.⁴⁵⁸ Foscarnet administration has been associated with changes in serum calcium, phosphorus, and magnesium values. In various studies involving patients with AIDS, elevations in serum calcium level have been reported in 27% to 79% of those treated, whereas decreases have been observed in 7% to 43%.^{381,441,447,449,452,459–464} The most probable mechanism for acute hypocalcemia is thought to involve chelation of the drug with ionized calcium.⁴⁶¹ Close monitoring of serum ionized calcium is very important, especially when there is concurrent usage of drugs, such as pentamidine, which may affect calcium homeostasis.⁴⁶² The effects of foscarnet on serum calcium and phosphorus levels (and secondarily on parathyroid hormone levels) are due additionally to sequestration of the drug in bone, and there may also be a role for the nephrotoxic effect of foscarnet in inhibiting renal phosphate secretion.^449,463

Anemia is the most common hematologic effect of foscarnet, with a fall in hemoglobin concentration occurring in 20% to 50% of patients with AIDS.^{381,448,456,464–466} Other adverse effects include nausea, vomiting, diarrhea, and abdominal pain.^{448,449,460,466} elevated hepatic enzymes,⁴⁵³ hallucinations, tremors and seizures,^{449,453,459,464} headaches,^449,453 nephrogenic diabetes insipidus,⁴⁶⁷ and genital and oral erosions possibly due to fixed drug eruptions or drug-induced contact dermatitis.^{381,468–470}

Foscarnet resistance in herpesviruses, including CMV, is due generally to a point mutation in the viral DNA polymerase.^9,470 In a prospective study, 26% of foscarnet treated patients had a resistant blood or urine culture isolate by 6 months of treatment, whereas less than 3% had positive cultures at the beginning of treatment for CMV retinitis. The probability of developing resistance to foscarnet was not significantly different from the development of resistance to ganciclovir or cidofovir while being treated with those agents.^470a

SYSTEMIC USES

Foscarnet has been used successfully and is superior to vidarabine in the treatment of acyclovir-resistant HSV infections,^{61,267,269,270,438,471} which have occurred predominantly in patients with AIDS. Foscarnet may also be effective in the treatment of acyclovir-resistant herpes zoster infections in patients with AIDS.^229,274,438 The dosage used in treating HSV and VZV infections (40 mg/kg every 8 hours) has often been lower than that used in treating CMV infections.

Foscarnet has been used to treat serious CMV infections in bone marrow and renal transplant recipients.^453,472,473 About two thirds of the patients in these uncontrolled trials have shown some improvement clinically and virologically, but not in mortality. It has also been used successfully to treat CMV gastrointestinal disease in patients with AIDS, including those who have failed ganciclovir therapy.^474,475 Foscarnet has a demonstrated anti-HIV effect as measured by decreases in the serum p24 antigen of HIV and HIV RNA levels, but whether this is of clinical significance remains to be determined.^{412,437,440,465,476,477} Foscarnet may also reduce the risk of Kaposi's sarcoma when used in HIV-associated CMV disease.⁴⁷⁸

OPHTHALMIC USES

Induction Therapy

Foscarnet appears to be about as effective as ganciclovir in the initial 2- to 3-week induction therapy of CMV retinitis in immunocompromised patients (predominantly those with AIDS).^{370,411,437,447,448,456,466} About 90% of such patients have had anatomic improvement or stabilization of CMV retinal lesions The induction dosage is administered as an intermittent infusion of 60 mg/kg every 8 hours or 90 mg/kg every 12 hours (which is preferred for convenience). Foscarnet does not cause neutropenia, thereby allowing full-dose zidovudine therapy, and it may have an inherent anti-HIV effect.^{411,412,437,440,476,477} Foscarnet therapy also has been effective in treating ganciclovir-resistant CMV retinitis,^445,446,464 and may be a reasonable alternative in treatment of acyclovir-resistant HZO in patients with AIDS.^229,274,438

Maintenance Therapy

As with ganciclovir, chronic maintenance therapy with foscarnet is required to treat CMV retinitis in patients with AIDS.^447,448 The optimal maintenance dosage has not been determined, but a dosage of 90 or 120 mg/kg once daily is generally used, with frequent adjustment for renal function.^{382a,411,457,459,464} Adequate intravenous hydration is critical during maintenance therapy.^437,455

Initial studies appeared to indicate that foscarnet maintenance was less effective than ganciclovir in preventing recurrent retinitis, but these studies used lower maintenance dosages of one third of the induction dose, or 60 mg/kg once on each of 5 days a week.^447,448,456 Palestine and associates⁴³⁷ performed a prospective randomized controlled trial of foscarnet in the treatment of CMV retinitis in AIDS patients. Foscarnet was administered in an induction dosage of 60 mg/kg every 8 hours for 3 weeks, followed by a maintenance regimen of 90 mg/kg once each day. By strict fundus photographic criteria, the mean time to progression of retinitis was increased from 3.2 weeks in controls to 13.3 weeks in those treated with foscarnet. This clearly demonstrated a beneficial effect of the drug and was comparable to results reported with ganciclovir. Preliminary evidence indicated that a dosage of 120 mg/kg/day in the pre-HAART era further delayed progression of retinitis without a substantial increase in nephrotoxicity, compared to 90 mg/kg/day.^459,479 There was some evidence for increased survival with the higher dosage.⁴⁵⁹ However, in the HAART era this possible survival benefit is probably not meaningful. Also, although it is likely that the higher dose is more efficacious, in the current era this may be of questionable benefit if the patient's immune system can be improved, and the benefit must be balanced against the trend toward increased renal and hypocalcemic events with the higher maintenance dose.^459,464 There may also be an increase in serious neurotoxicity, including seizures, with this higher dosage that is possibly related to low serum levels of ionized calcium.^437,461,464 This can occur despite normal total serum calcium concentrations.⁴⁶¹ The higher maintenance dose is probably best reserved for patients with potential vision-threatening disease or those who are unlikely to respond to HAART or who are receiving monotherapy for recurrent disease and are tolerating foscarnet well.

Foscarnet therapy in the pre-HAART era could prolong life in patients with AIDS compared to ganciclovir treatment because of its anti-HIV effect and the ability to use it in conjunction with zidovudine.^437,476 However, because of its metabolic and nephrotoxic effects, foscarnet use requires closer monitoring and more frequent dosage adjustment than does ganciclovir.

SOCA Studies

In the pre-HAART era, the SOCA research group performed a randomized multicenter trial that compared foscarnet with ganciclovir for the initial treatment of CMV retinitis in 234 patients with AIDS.⁴¹¹ Patients received 2 weeks of induction therapy with either foscarnet (60 mg/kg every 8 hours) or ganciclovir (5 mg/kg every 12 hours). This was followed by maintenance therapy with foscarnet (90 mg/kg/day, which was increased to 120 mg/kg after repeat induction for relapse of retinitis) or ganciclovir (5 mg/kg/day). The two drugs were equally effective in treating CMV retinitis (median time to progression was 47 days for ganciclovir and 53 days for foscarnet). As noted in the the section on ganciclovir, 85% of patients in both groups had progressed by 120 days, indicating the inevitability of this event in the pre-HAART era.³⁷⁰ There was a 4-month median survival advantage to initial treatment with foscarnet (12.6 months) compared with ganciclovir (8.5 months), except in a subgroup of patients who entered the study with mildly decreased renal function. This difference could not be fully explained by the increased zidovudine usage in the foscarnet group. It was believed likely due to a direct antiretroviral effect of foscarnet, although both drugs were shown to reduce serum HIV p24 antigen levels.⁴¹² These findings should be tempered by the fact that foscarnet was far less well tolerated than ganciclovir, with many more patients switching from foscarnet to ganciclovir due to toxicity than vice versa (46% vs. 11%).³⁸¹ Since in the HAART era this survival benefit of foscarnet is not important, and since it was not present in the subsequent CMV retinitis retreatment trial, ganciclovir is considered the drug of choice. It is equally effective and much better tolerated.

Because of in vitro evidence for the additive or synergistic effects on CMV of combination foscarnet and ganciclovir,^480,481 there was interest in using the two drugs together, especially since the first SOCA trial demonstrated that subsequent progression of disease occurred at progressively shorter intervals after re-induction with either drug.³⁷⁰ To evaluate whether further relapse could be reduced by combination therapy as opposed to higher (and more toxic) doses of an individual drug, SOCA sponsored the CMV Retinitis Retreatment Trial.^382a Patients who had relapsed with either drug were randomly assigned to receive monotherapy with (1)either an induction course of ganciclovir 5 mg/kg twice daily for 2 weeks followed by a 10 mg/kg maintenance dose, or the standard regimen of foscarnet 90 mg/kg twice daily for 2 weeks followed by 120 mg/kg daily; or (2) combination therapy in which the patient continued his current maintenance drug and received standard induction therapy with the other drug followed by combination maintenance (ganciclovir 5 mg/kg/day plus foscarnet 90 mg/kg/day). The results demonstrated that combination therapy produces a longer median remission (4.3 months) than either ganciclovir alone (2 months) or foscarnet alone (1.3 months), as well as less loss of visual field. There were no differences in survival between the groups (i.e., no survival benefit of foscarnet). Combination therapy, however, as one might expect, adversely affected the quality of life. The implications of these results in the HAART era as well as the options of the ganciclovir implant and oral valganciclovir are discussed in the section on ganciclovir.

Foscarnet can also be administered via intravitreal injection for progressive disease when the patient is unresponsive to or intolerant of other therapies. Doses used have been 1.2 mg and 2.4 mg/0.1 mL.^482,483 The half-life of foscarnet has been estimated to be 32 hours, with vitreous levels above the mean 50% inhibition value of CMV at 41 hours with the lower dosage.⁴⁸⁴ Vitreous levels in one patient at the higher dosage at 42.5 hours were 749 μmol/L. Although there is less experience than with intravitreal ganciclovir, the efficacy and toxicity appear to be comparable.⁴⁸³ It is generally given as 2 injections weekly for 3 weeks induction followed by once-weekly maintenance.

MECHANISM OF ACTION, PHARMACOLOGY, AND TOXICITY

Cidofovir (1-[(s)-3-hydroxy-2-(phosphonomethoxy)-propyl] cytosine dihydrate) is a cytidine nucleotide analog with inhibitory activity against herpesviruses, including HSV-1 and -2, VZV, CMV, EBV, and HHV-8, as well as other DNA viruses such as papilloma, polyoma, pox, and adenoviruses.^485–487 Because cidofovir as a phosphonate possesses a phosphate group, it does not require phosphorylation by virus-encoded enzymes. It may therefore be effective against herpesvirus mutants that do not phosphorylate acyclovir or ganciclovir. It is converted to its active diphosphate (which has three phosphate groups) by cellular kinases, achieving similar concentrations in virus-infected and uninfected cells. Cidofovir diphosphate selectively inhibits CMV and HSV DNA polymerases at concentrations 8- to 600-fold lower than those required to inhibit human DNA polymerases.^485,488,489 Viral DNA polymerase incorporates cidofovir diphosphate into the growing viral DNA chain, instead of deoxycytosine triphosphate, reducing the rate of DNA synthesis.⁴⁸⁹ Cidofovir diphosphate has a prolonged intracellular half-life of up to 65 hours. A phosphocholine metabolite has an intracellular half-life of 87 hours and may serve as an intracellular reservoir for cidofovir diphosphate. Cidofovir in combination with ganciclovir or foscarnet produced additive or synergistic in vitro inhibition of CMV.^489,490

Cidofovir has poor oral bioavailability (<5%). It is administered intravenously over 1 hour via infusion pump at weekly (induction) to biweekly (maintenance) intervals with concomitant saline hydration and oral probenicid to ameliorate potentially severe nephrotoxicity.^489,491,492 Plasma levels decline in a biphasic manner with a terminal half-life of 2.6 hours.⁴⁹¹ The prolonged dosing interval is a result of the long intracellular half-life of cidofovir diphosphate, as noted above. Cidofovir is eliminated almost entirely as unchanged drug in the urine via glomerular filtration and active tubular secretion. High-dose oral probenicid (before and after infusion) blocks tubular transport of cidofovir, reducing renal clearance and associated nephrotoxicity while increasing plasma concentrations. The plasma half-life increases to 32.5 hours in patients on dialysis. Dialysis removes over 50% of the administered dose. Penetration into cerebrospinal fluid is negligible under normal circumstances.⁴⁹¹

The recommended regimen for patients with AIDS-associated CMV retinitis and adequate renal function is 5 mg/kg intravenously weekly for 2 weeks induction followed by 5 mg/kg every 2 weeks maintenance. To reduce the risk of renal dysfunction, at least 1 liter of normal saline should be infused over 1 to 2 hours prior to each dose and, in those patients who can tolerate additional fluid, a second liter should be infused at the beginning or end of cidofovir infusion. Also, oral probenicid must be co-administered as 2 g 3 hours before and 1 g 2 and 8 hours after each infusion. Cidofovir is contraindicated in patients with serum creatinine greater than 1.5 mg/dL, calculated creatinine clearance less than 55 mL/minute, or proteinuriq of 2+ or more. Other nephrotoxic drugs (e.g., foscarnet, amphotericin B, intravenous pentamidine, non-steroidal anti-inflammatory drugs, vancomycin) should not be administered within 7 days of cidofovir treatment. Monitoring of serum creatinine and urine protein is mandatory prior to each dose and, because cidofovir is potentially toxic to bone marrow, monitoring of white blood cell counts with differential is also recommended. Intraocular pressures should be measured at baseline and on a regular basis, with discontinuation of cidofovir if it falls by 50%.⁴⁸⁹ The cidofovir dosage should be reduced to 3 mg/kg in patients who have an increase in serum creatinine of 0.3 to 0.4 mg/dL or persistent 2+ proteinuria, and discontinued if there is a greater increase in serum creatinine or the development of 3+ or greater proteinuria.

The major adverse effects of cidofovir are nephrotoxicity and ocular toxicity (uveitis and/or hypotony), with many patients also unable to tolerate probenicid. This has resulted in difficulty with long-term tolerance of cidofovir. Data from the manufacturer and pooled data from the first three clinical trials leading to FDA approval^{489,493–495} indicated that 20% to 25% of patients receiving the recommended maintenance dosage of 5 mg/kg every 2 weeks discontinued treatment due to adverse effects. A long-term follow-up of one of these trials performed by the SOCA group found the median time to discontinuation of the drug due to intolerance to be 6.6 months (16.3 months for reasons besides probenicid toxicity) with rates of 2+ proteinuria or more of 1.22/person-year, neutropenia of 0.30/person-year, and cidofovir-associated uveitis of at least 0.20/person-year (a higher rate than the manufacturer reports).⁴⁹⁶ Pooled data from the manufacturer reported adverse events including nephrotoxicity (22.4%), uveitis/iritis (10.1%), hematologic abnormalities (9.7%), nausea/vomiting (9.1%), fever (6.2%), and skin rash/pruritis (4.2%). A more recent study found the rate of nephrotoxicity to be 0.48/person-year with three of 30 patients requiring dialysis.⁴⁰⁶ Probenicid, required to limit nephrotoxicity, commonly causes adverse events, including nausea/vomiting, fever, and rash.^{489,493–496} Cidofovir-induced nephrotoxicity is dose-dependent and is the result of tubular cell injury. It is usually at least partially reversible with discontinuation, but acute renal failure can occur.^406,489,496 It has been associated with cases of nephrogenic diabetes insipidus, metabolic acidosis, and Fanconi's syndrome.⁴⁸⁹

The rate of ocular complications, especially anterior uveitis, has increased markedly with post-marketing surveillance. Acute anterior uveitis, which is often severe and may develop synechiae or hypopyon, has been reported in between 25% and 59% of patients in different series.^{406,496–499} It is estimated to occur in up to 50% of patients by 125 days,⁴⁹⁷ and a recent clinical trial of cidofovir reported a rate of 0.35/person-year.⁴⁰⁶ Most cases occurred after 4 to 5 doses^497,498 (although in one study the median was 11 doses⁴⁹⁹) typically 4 or 5 days following cidofovir infusion.^497,499 Many cases have responded to topical corticosteroids and cycloplegics, although uveal effusion and vision loss can occur.^497–499 It can be bilateral, but in unilateral cases generally occurs in the eye involved by CMV retinitis. The cause is undetermined. Although there is apparently a toxic effect of cidofovir on the ciliary body (postulated also to be responsible for hypotony⁵⁰⁰), there seems to be a relation to improved immune response, becauses the uveitis has been variably related to use of protease inhibitors^406,496,497 and elevations in CD4 count.⁴⁹⁹ Hypotony both with and, occasionally, without iritis⁵⁰¹ may also occur in about 10% of patients⁴⁹⁷ at an estimated rate of 0.16/person-year.⁴⁹⁶ It can be associated with choroidal effusion, macular edema, and vision loss.^497,498,501 Intravitreal injections of cidofovir have shown toxic effects on the ciliary body.^500,502,503

Cidofovir was associated with mammary adenocarcinoma in rats and is considered a potential human carcinogen, although there has not been an increase in malignancies in cidofovir recipients.⁵⁰⁴ It may cause infertility and is contraindicated in pregnancy.

Ganciclovir-resistant isolates of CMV with mutations in the UL97 gene remain susceptible to cidofovir.³³⁷ However, highly ganciclovir-resistant clinical isolates of CMV that possess both DNA polymerase mutations and UL97 gene mutations show cross-resistance to cidofovir.³³⁸ Triple drug–resistant variants (to ganciclovir, foscarnet, and cidofovir) have been described.³³⁷ In a prospective study of patients with CMV retinitis, 29% of cidofovir-treated patients had a resistant blood or urine culture by 3 months of therapy, which was similar to the risk of resistance with ganciclovir or foscarnet.^470a

SYSTEMIC USES

Intravenous cidofovir is approved only for the treatment of CMV retinitis in AIDS patients. Its efficacy and tolerability are unproved in other CMV diseases or in non-HIV settings. Successful use of cidofovir in the treatment of acyclovir-resistant mucocutaneous HSV infections has been reported anecdotally.²⁷¹ Cidofovir is effective against monkey pox virus and has in vitro activity against smallpox.⁵⁰⁵ Therefore, although there is no clinical experience, in view of the planned re-introduction of smallpox vaccine, its use should be considered for the treatment of progressive or generalized vaccinia or in severe cases of smallpox in the event of an outbreak.⁵⁰⁶

OPHTHALMIC USES

Intravenous cidofovir is approved for the treatment of CMV retinitis in AIDS patients at a dosage of 5 mg/kg once a week for 2 weeks induction, and then every 2 weeks for maintenance therapy. This prolonged dosing interval obviates the need for an indwelling catheter.

Three randomized controlled trails have demonstrated its efficacy in delaying the progression of AIDS-related CMV retinitis in both newly diagnosed patients^493,494 and patients with persistently active or relapsing retinitis despite therapy with intravenous ganciclovir or foscarnet.⁴⁹⁵ All three trials used the standard induction regimen. Two were performed in newly diagnosed patients with peripheral retinitis. One of these, sponsored by the manufacturer,⁴⁹³ found that the standard 5 mg/kg biweekly maintenance dose delayed the median times to progression to 120 days from 22 days with deferral of treatment. The other trial, performed by the SOCA group, compared maintenance doses of 3 mg/kg and 5 mg/kg every 2 weeks with deferral.⁴⁹⁴ Both doses seemed effective. The median time to progression with the 3 mg/kg dose was 64 days and was not reached with the 5 mg/kg dose, while progression occurred in 20 to 21 days in the deferral groups. The third trial, performed on patients with relapsing CMV retinitis previously treated with ganciclovir and/or foscarnet, compared the 5 mg/kg and 3 mg maintenance regimens. The higher maintenance dose was found to significantly delay disease progression (median time not reached) compared to the lower dose (median time 49 days).⁴⁹⁵ The conclusions drawn from these studies was that cidofovir is effective in treating CMV retinitis and that the higher maintenance dose (the approved dose) is more effective but also probably has increased toxicity.

A long-term follow-up of the SOCA study beyond the time of randomization revealed overall the median time to progression to be 2.5 months, confirming efficacy.⁴⁹⁶ However, it also confirmed the relatively poor long-term tolerability of the drug. The median time to discontinuation of cidofovir due to intolerance was 6.6 months, although much of this was caused by probenicid intolerance. A curiosity of the first three randomized studies was failure to recognize the now well-characterized cidofovir-associated anterior uveitis. This longer-term follow-up revealed that in retrospect this uveitis did occur and at a rate of at least 0.20/person-year.

A possible concern with cidofovir as treatment of CMV retinitis is that although it causes a marked reduction in CMV-positive urine cultures,^493,494 it has been less effective in reducing CMV viremia.^492–494 This has not, however, translated into any reported effect on survival or systemic CMV disease. A small study of combination intravenous ganciclovir and oral ganciclovir did demonstrate a marked reduction in CMV viremia but an unacceptable incidence of ocular toxicity.⁵⁰⁷ Although there have been no head-to-head studies of cidofovir versus systemic ganciclovir or foscarnet, it seems to have equivalent efficacy for CMV retinitis.^496,508

A randomized controlled study was performed by SOCA investigators comparing intravenous cidofovir with the ganciclovir implant plus oral ganciclovir as a comparison of the two catheterless options available at the time⁴⁰⁶ (discussed in the secion on ganciclovir). In essence, the study demonstrated that in patients who were predominantly on HAART therapy, the two regimens were equally effective, but that cidofovir was less well tolerated. It is not known how cidofovir compares to oral valganciclovir. It is of interest that the rate of uveitis with cidofovir (0.35/person-year) was higher than in the previous SOCA study, possibly due to increased use of HAART but also possibly due to increased awareness of this entity.

Intravitreal injections (20 μg) of cidofovir were performed in a single center consecutive case series that reported good control of CMV retinitis when given at 5- to 6-week intervals.^500,509 Oral probenicid was used to reduce the incidence of iritis and hypotony by possibly blocking uptake in the ciliary body. However, serious complications did occur in patients.^502,503 A lower dose (10 μg) was found minimally effective.⁵¹⁰ The formulation used in these studies was not the commercially available preparation, and dosages may not be comparable. A multicenter clinical trial sponsored by the manufacturer evaluating 5-, 10-, and 15-μg doses was halted after only 31 patients were enrolled because of severe toxicity (mainly uveitis and hypotony) with minimal efficacy.^489,511 The manufacturer considers intraocular injections of cidofovir to be contraindicated, and clinicians are strongly discouraged against such use.⁴⁸⁹

In the HAART era, intravenous cidofovir provides a catheter-free alternative to the ganciclovir implant in patients with CMV retinitis who have the potential for immune reconstitution and are intolerant of systemic ganciclovir. Its use is limited by its toxicity. Careful monitoring for renal and ocular toxicity is necessary, with appropriate reduction in dose to 3 mg/kg or discontinuation if proteinuria and/or elevated serum creatinine levels develop.

Cidofovir has in vitro activity against adenoviral types which cause keratoconjunctivitis.⁵¹² In a randomized controlled trial, cidofovir 1% eye drops reduced the frequency of severe corneal opacities but had unacceptable local toxicity when used with or without topical cyclosporine. It caused conjunctival pseudomembranes and erythematous inflammation of the skin of the eyelids and worsened conjunctivitis.⁵¹³ Intraocular pressures were not monitored. A previous study had shown cidofovir drops in a lower concentration of 0.2% to be ineffective.⁵¹⁴

MECHANISM OF ACTION, PHARMACOLOGY, AND TOXICITY

Fomivirsen sodium is a 21-base synthetic phosphorothioate oligonucleotide (5'-GCG TTT GCT CTT CTT CTT GCG-3') complementary to the mRNA sequence that encodes for the major immediate-early region (IE2) proteins of CMV.⁵¹⁵ Binding to this location inhibits gene expression essential for CMV replication (a sequence-dependent antisense mechanism) without interfering with the functioning of human genes. It also inhibits adsorption of CMV to host cells (a sequence-independent mechanism).^519,520 In cell culture, fomivirsen was 30- to 90-fold more potent than ganciclovir against CMV. The mean 50% effective concentration (EC₅₀) was 0.37 μmol/L, and a concentration of 2.2 μmol/L produced 99% inhibition of infectious human CMV.^515,519 The specific nature of its mechanism of action renders it, in theory, ineffective against other viruses. Its anti-CMV activity is additive with ganciclovir or foscarnet, and it is active against CMV strains resistant to other agents.^516,521,522

Following intravitreal injection, the half-life of elimination from the vitreous is 55 hours with metabolism (presumably via retinal nuclease digestion) apparent in the vitreous by 2 days. Exposure in the vitreous at 1 hour was 5.5 and 11.6 μmol/L following 165- and 330-μg injections, respectively.^515,523 The decrease in fomivirsen vitreous concentration is assumed to be due partly to uptake into the retina and other ocular tissues, in addition to outflow through the anterior chamber and nuclease metabolism. Fomivirsen concentrations in the rabbit retina increased and declined more gradually than in the vitreous with significant concentrations 10 days after administration with a half-life of 72 hours.^516,524 Fomivirsen is undetectable in the plasma following intravitreal injection.^515,523

Pooled data from the manufacturer's database reveal the most common adverse events to be elevated intraocular pressure (12% to 20%) and intraocular inflammation including anterior chamber inflammation (10% to 20%), vitritis (10% to 12%), and “uveitis” (5% to 10%).⁵¹⁶ These complications generally have responded to topical therapy. Cataracts occurred in 7% to 14% of patients.^516,525 The frequency of these and other complications have been dose- and schedule-dependent.⁵²⁵ For instance, in a subgroup of patients receiving the more intensive regimen of 330 μg 3 times weekly and then every 2 weeks, elevated intraocular pressure occurred in 28%. Overall, the 330-μg dose resulted in a rate of ocular inflammation of 0.87/person-year when given in the FDA-approved regimen of 2 doses 14 days apart and then every 4 weeks, but the rate increased to 1.88/person-year in the more intensive regimen.^518,525 A potentially more troubling adverse effect is retinal pigment epitheliopathy. It has manifested as varying combinations of retinal pigmentary changes, nyctalopia, visual field loss, and abnormal electroretinograms (ERGs).^525–528 There is also a report of a reversible bull's eye maculopathy.⁵²⁹ An early study of the 330-μg dose regimen for initial treatment of CMV retinitis was halted due to a 45% incidence of retinal pigment epitheliopathy.⁵²⁵ Subsequent studies showed it to be much less common,⁵²⁵ but visual fields and electrophysiologic studies have not been performed routinely and follow-up has been relatively short.⁵¹⁸ Although it is not clear to what degree this toxicity results in a functional deficit, pre-clinical studies have suggested a narrow therapeutic index,^517,522 and careful observation is warranted. Fomivirsen use is also subject to potential adverse effects associated with repeated intravitreal injections such as infection, hemorrhage, and retinal detachment. The manufacturer recommends that fomivirsen not be administered for 2 to 4 weeks after the use of intravenous cidofovir to avoid a possible increased risk of uveitis.

OPHTHALMIC USES

Fomivirsen's only current use is as second-line therapy of CMV retinitis in AIDS patients. It was envisioned as a viable alternative to chronic intravenous therapy and the ganciclovir implant at a time before effective oral therapy of CMV or therapy that could reduce the underlying HIV-induced immunodeficiency was available. The advent of oral valganciclovir and especially highly active antiretroviral therapy (HAART), however, has limited the situations in which it should be used.

Intravitreal fomivirsen was demonstrated in a multicenter controlled clinical trial to be effective in delaying the progression of newly diagnosed peripheral CMV retinitis when used at a dosage of 165 μg weekly for 3 weeks induction, followed by every-other-week maintenance therapy. Progression occurred at a median of 71 days in the immediate treatment group compared to 13 days in the deferral of treatment group (P = 0.0001).⁵³⁰

For the treatment of CMV retinitis that had reactivated or progressed despite treatment with another anti-CMV drug, two different regimens were each compared in two separate studies (the USA/Brazilian study and the Euro-Canadian study).⁵³¹ Each compared a fomivirsen dosage of 330 μg in a more intensive regimen A (3 weekly injections as induction followed by injection every 2 weeks as maintenance therapy) with a less intensive regimen B (injection at day 1 and 15 and then every 4 weeks). Efficacy was similar for both regimens in both studies. The median times to progression in the USA/Brazilian study were 106 days for regimen A and 267 days for regimen B (P = 0.2179). In the Euro-Canadian study, the median time to progression was not determinable for regimen A and was 403 days for regimen B. One must bear in mind that HAART therapy became available during the course of these studies and had a likely influence on the prolonged times until progression of disease as well as on the differing results between the studies. There was also a differential use of oral ganciclovir in these studies.

In 1998, the FDA approved a less intensive regimen of 330 μg on days 1 and 14 followed by monthly inections as maintenance, presumably because it was equally effective while being safer and more convenient.^518,525,531 It is approved for treatment of CMV retinitis in AIDS patients who are intolerant of, have a contraindication to, or were insufficiently responsive to other treatments. It should not generally be used for initial treatment. If one is tempted to use it for initial treatment in special circumstances (e.g., for a patient with pancytopenia and renal failure who is not considered to be a candidate for a ganciclovir implant), it should be remembered that the study demonstrating efficacy as initial treatment of peripheral retinitis used a smaller dose (165 μg) than the FDAapproved dose. As noted previously, an early study of the 300-μg dose for initial treatment was aborted due to an unacceptably high rate of retinal pigment epitheliopathy. Whenever possible, patients treated with intravitreal fomivirsen should also receive systemic therapy with oral valganciclovir or ganciclovir to prevent contralateral eye disease and visceral disease. Combination therapy is also more likely to be effective. The major role of intravitreal fomivirsen will probably be as an alternative to the ganciclovir implant in patients who are believed to have the potential for recovery of their immune system with HAART therapy. It has an advantage over intravitreal ganciclovir or foscarnet in having a more convenient dosing schedule, but it may also be more toxic.⁵¹⁸

Table 2. Anti-Retrovital Agents for HIV Infection

Nucleoside Reverse Transcriptase Inhibitors
  Abacavir (ABC, Ziagen)
  AZT 1 3TC (Combivir)
  Didanosine (DDI, Videx/Videx EC [enteric-coated])
  Emtricitabine (FTC, Coviracil)^a
  Lamivudine (3TC, Epivir)
  Stavudine (d4T, Zerit)
  Tenofovir (TNV, Viread).
  Zalcitabine (DDC, Hivid)
  Zidovudine (AZT, ZDV)
Protease Inhibitors
  Atazanavir^a
  Amprenavir (AMP, Agenerase)
  Indinavir (IDV, Crixivan)
  Lopinavir (LPV/RTV, Kaletra)
  Mozenavir (DMP 450)
  Nelfinavir (NFV, Viracept)
  Ritonavir (RTV, Norvir)
  Saquinavir (FTV, Fortavase [soft-gel capsule] or INV, Invirase[hard-gel capsule])
Non-Nucleoside Reverse Transcriptase Inhibitors
  Delaviridine (DLV, Rescriptor)
  Efavirenz (EFV, Sustiva)
  Nevirapine (NVP, Viramune)
Entry Inhibitors
  T-20 (enfuvirtide, Fuzeon)<sup>a

a</sup>Experimental agents that are in active clinical trials and are likely to be approved by the Federal Drug Administration within a year.

In the HAART era, CMVR also may remain quiescent despite extremely low CD4 cell counts, and rarely CMVR may become active in the setting of persistently high CD4 cell counts in HAART responders.^546,549 Jacobson and associates observed that patients with positive CMV-specific immune responses by lymphoproliferation or cytokine flow cytometry may be at risk for future CMV disease progression, and they should be closely monitored.⁵⁵⁰ The 2002 USPHS/IDSA guidelines recommend that discontinuation of maintenance treatment be considered in patients with sustained (6 months) increase in CD4 to greater than 100 to 150 cells/μL in response to HAART, after taking into consideration the magnitude and duration of CD4 increase, the anatomic location of the retinitis, vision in the contralateral eye, and the feasibility of regular ophthalmologic monitoring. Frequent monitoring of immune status is necessary if anti-CMV therapy is withdrawn, and re-initiation of therapy may be advisable if CD4 counts fall to less than 100 to150 cells/μl.³⁹¹ (See Table 3.)

Table 3. Approach for the Patient with AIDS and CMV Retinitis

In the pre-HAART era, patients with CMVR had minimal intraocular inflammation and rarely had macular edema. Significant intraocular inflammation has been reported in the affected eye of some patients with healed or still active CMVR who are receiving HAART. Findings variably include iritis, cataract, vitritis, cystoid macular edema, and optic disc edema and are referred to as immune recovery uveitis.^551–554 Eyes with CMVR involving a surface area greater than 30% of the retina are at higher risk.⁵⁵⁵ The vision loss associated with immune recovery uveitis often results from cystoid macular edema and epiretinal membrane formation.^551–555 Treatment with topical, periocular, or systemic corticosteroids has had variable success in some patients with immune recovery uveitis and cystoid macular edema.^{551,553–556} Surgery may be needed for severe epiretinal membranes or retinal detachments. ^554–556 Published incidence estimates have varied between 0.11/person-year and 0.83/person-year.^552,554 A recent study estimated the frequency among prevalent cases of CMVR to be 15.5%, which is more consistent with the lower incidence estimate.⁵³⁵

Lobucavir (carbocyclic oxetanocin-G; cyclobut-G) is a synthetic guanine nucleoside analog with in vitro activity against a broad range of herpesviruses, hepatitis B virus (HBV), and HIV.⁵⁶⁰ It inhibits viral DNA synthesis and is preferentially phosphorylated in HSV-infected cells to the active triphosphate, with lower concentrations of lobucavir triphosphate in CMV-infected and in uninfected human cells.⁵⁶¹ The drug is formulated as oral capsules as well as for intravenous use.

Oral lobucavir has shown antiviral activity in CMV- and HBV-infected patients and clinical benefit in HSV infections of immunocompetent hosts. Doses of 200 and 400 mg four times a day are associated with suppression of CMV viruria in HIV-infected persons.⁵⁶² A dosage of 200 mg twice a day reduces healing time and pain in patients with recurrent genital herpes.⁵⁶³

BAY 38-4766 and its main metabolite, BAY 43-9695, are new investigational non-nucleoside compounds with in vitro activity against CMV. Both compounds block virus replication by inhibiting the cleavage of polygenomic viral DNA, i.e., interfering with DNA maturation and packaging of monomeric genomic lengths.^564,565 Benzimidavir (Moribavir, or 1263W94), a benzimadazole derivative, is a new investigational agent for CMV and EBV infection. It has a novel mechanism of action, inhibiting viral DNA synthesis via UL97 protein kinase (blocking terminal DNA processing).⁵⁶⁶ The drug is active in human CMV isolates resistant to ganciclovir or foscarnet.⁵⁶⁷In vitro, it demonstrates synergy with foscarnet and cidofovir.

Clinical trials with these new agents are ongoing.

1. Kaufman HE, Nesburn AB, Maloney ED: IDU therapy of herpes simplex. Arch Ophthalmol 67:483, 1962.

2. Kaufman HE, Martola E, Dohlman C: Use of 5-iodo-2-deoxyuridine (IDU) in treatment of herpes simplex keratitis. Arch Ophthalmol 68:235, 1972.

3. Patterson A, Fox AD, Davies G et al: Controlled studies of IDU in the treatment of herpetic keratitis. Trans Ophthalmol Soc UK 83:583, 1963.

4. Burns RP: A double-blind study of IDU in human herpes simplex keratitis. Arch Ophthalmol 70:381, 1963.

5. Laibson PR, Leopold IH: An evaluation of double-blind IDU therapy in 100 cases of herpetic keratitis. Trans Am Acad Ophthalmol Otolaryngol 68:22, 1964.

6. Maxwell E: Treatment of herpes keratitis with 5-iodo-2-deoxyuridine (IDU): A clinical evaluation of 1500 cases. Am J Ophthalmol 56:571, 1963.

6a. DeClerq E, Descamps J, Verhelst G et al: Comparative efficacy of antiherpes drugs against different strains of herpes simplex virus. J Infect Dis 141:563, 1980.

7. Prusoff WH: Idoxuridine or how it all began. In DeClerq E (ed): Clinical Use of Antiviral Drugs, pp 15–24. Norwell, MA, Martinus Nijoff, 1988.

8. Prusoff WH, Chang PK: 5-Iodo-2'-deoxyuridine 5'-triphosphate, an allosteric inhibitor of deoxycytidilate deaminase. J Biol Chem 243:223, 1968.

9. Boston Interhospital Viral Study Group: Failure of high-dose 5-iodo-2'-deoxyuridine in the therapy of herpes simplex virus encephalitis: Evidence of unacceptable toxicity. N Engl J Med 292:599, 1975.

10. Kaufman HE, Maloney ED: Virus chemotherapy with antimetabolites. Pharmakotherapia 1:43, 1963.

11. Maloney ED, Kaufman HE: Antagonism and toxicity of IDU by its degradation products. Invest Ophthalmol 2:55, 1963.

12. Foster CS, Pavan-Langston D: Corneal wound healing and antiviral medication. Arch Ophthalmol 95:2062, 1977.

13. Pavan-Langston D, Langston RHS: Recent advances in antiviral therapy. Int Ophthalmol Clin 15:89, 1975.

14. Stern GA, Killingworth DW: Complications of topical antimicrobial agents. Int Ophthalmol Clin 29:137, 1989.

15. Wilson FM II: Adverse external ocular effects of topical ocular medications. Surv Ophthalmol 24:57, 1979.

16. Kaufman HE: Treatment of viral diseases of the cornea and external eye. Prog Retinal Eye Res 19:69, 2000.

17. Itoi M, Getter JW, Kaneko N et al: Teratogenicities of ophthalmic drugs: Antiviral ophthalmic drugs. Arch Ophthalmol 93:46, 1975.

18. Wellings PC, Awdry PN, Bors FH et al: Clinical evaluation of trifluorothymidine in the treatment of herpes simplex corneal ulcers. Am J Ophthalmol 73:932, 1972

19. Pavan-Langston D, Foster CS: Trifluorothymidine and idoxuridine therapy of ocular herpes. Am J Ophthalmol 84:818, 1977.

20. Laibson PR, Arentsen JJ, Mazzanti WD et al: Double controlled comparison of IDU and trifluorothymidine in thirty-three patients with superficial herpetic keratitis. Trans Am Ophthalmol Soc 75:316, 1977.

21. McGill J, Holt-Wilson AD, McKinnon JR et al: Some aspects of the clinical use of trifluorothymidine in the treatment of herpetic ulceration of the cornea. Trans Ophthalmol Soc UK 94:342, 1974.

22. Pavan-Langston D, Dohlman CH: A double-blind clinical study of adenine arabinoside therapy of viral keratoconjunctivitis. Am J Ophthalmol 74:81, 1972.

23. Dresner AJ, Seamans ML: Evidence of the safety and efficacy of adenine arabinoside in the treatment of herpes simplex epithelial keratitis. In Pavan-Langston D, Buchanon RA, Alford CA Jr (eds): Adenine Arabinoside: An Antiviral Agent, pp 381–391. New York, Raven Press, 1975.

24. Pavan-Langston D, Buchanon RA: Vidarabine therapy of simple and IDU-complicated herpetic keratitis. Trans Am Acad Ophthalmol Otolaryngol 81:813, 1976.

24a. Wilhelmus KR: The treatment of herpes simplex virus epithelial keratitis. Tr Am Ophthalmol Soc 98:505, 2000.

25. Coleman VR, Tsu E, Jawetz E: Treatment resistance to idoxuridine in herpetic keratitis. Proc Soc Exp Biol Med 129:761, 1968.

26. Dubbs DR, Kit S: Mutant strains of herpes simplex deficient in thymidine kinase-inducing activity. Virology 22:493, 1964.

27. Gottschling H, Heidelberger C: Fluorinated pyrimidines: XIX. Some biological effects of 5-trifluoromethyl-2'-deoxyuridine on Escherichia coli and bacteriophage T4B. J Mol Biol 7:541, 1963.

28. Prusoff WB, Zucker M, Mancini WR et al:. Basic biochemical and pharmacological aspects of antiviral agents.. Antiviral Res 5:1, 1985.

29. Kaufman HE, Heidelberger C: Therapeutic antiviral action of 5-trifluoromethyl-2'-deoxyuridine. Science 145:585, 1964.

30. Hyndiuk RA, Kaufman HE: Newer compounds in the therapy of herpes simplex keratitis. Arch Ophthalmol 78:600, 1967.

31. Collins P, Bauer D: Relative potencies of antiherpes compounds. Ann N Y Acad Sci 26:49, 1977.

32. Hyndiuk RA, Seidman S, Leibsohn JM: Treatment of vaccinial keratitis with trifluorothymidine. Arch Ophthalmol 94:1785, 1976.

33. Spector SA, Tyndall M, Kelley E: Inhibition of human cytomegalovirus by trifluorothymidine. Antimicrob Agents Chemother 23:113, 1983.

34. Lennette DA, Eiferman RA: Inhibition of adenovirus replication in vitro by trifluoridine. Arch Ophthalmol 96:1662, 1978.

35. Pavan-Langston D, Nelson DJ: Intraocular penetration of trifluridine. Am J Ophthalmol 87:814, 1979.

36. Obrien W, Edelhauser H: The corneal penetration of trifluorothymidine, adenine arabinoside, and idoxuridine: A comparative study. Invest Ophthalmol Vis Sci 16:1093, 1977.

37. Poirer RH, Kingham JD, DeMiranda P et al: Intraocular antiviral penetration. Arch Ophthalmol 100:1964, 1982.

38. Carmine AA, Brogden RN, Heel RC et al: Trifluoridine: A review of its antiviral activity and therapeutic use in the topical treatment of viral eye infections. Drugs 23:329, 1982.

39. Coster DJ, McKinnon JR, McGill JI et al: Clinical evaluation of adenine arabinoside and trifluorothymidine in the treatment of corneal disease caused by herpes simplex virus. J Infect Dis 133:A173, 1976.

39a. Udell IJ: Trifluridine-associated conjunctival cicatrization. Am J Ophthalmol 99:363, 1985.

40. Shearer DR, Bourne WM: Severe ocular anterior segment ischemia after long-term trifluridine treatment for presumed herpetic keratitis. Am J Ophthalmol 109:346, 1990.

40a. Maudgal PC, Van Damme B, Missotten L: Corneal epithelial dysplasia after trifluridine use. Graefes Arch Clin Exp Ophthalmol 220:6, 1983.

41. Pang MP, Peyman GA, Nikoleit J et al: Intravitreal trifluorothymidine and retinal toxicity. Retina 6:260, 1986.

42. Ansfield FJ, Ramirez G: Phase I and II studies of 2-deoxy-5-(trifluoromethyl)-uridine (NSC-75520). Cancer Chemother Rep 55:205, 1971.

43. Kury G, Crosby RJ: The teratogenic effect of 5-trifluoromethyl-2'-deoxyuridine in chicken embryos. Toxicol Appl Pharmacol 11:72, 1967,

44. Jones BR, McGill JI, McKinnon JR et al: Preliminary experience with adenine arabinoside in comparison with idoxuridine and trifluorothymidine in the management of herpetic keratitis. In Pavan-Langston D, Buchanon RA, Alford CA (eds): Adenine Arabinoside: An Antiviral Agent, pp 411–416. New York, Raven Press, 1975.

45. Sugar J, Stark W, Binder PS et al: Trifluorothymidine treatment of herpes simplex epithelial keratitis and comparison with idoxuridine. Ann Ophthalmol 12:611, 1980.

46. Parlato CJ, Cohen EJ, Sakauye CM et al: Role of débridement and trifluridine (Trifluorothymidine) in herpes simplex dendritic keratitis. Arch Ophthalmol 103:673, 1985.

47. Van Bijsterveld OP, Post H: Trifluorothymidine versus adenine arabinoside in the treatment of herpes simplex keratitis. Br J Ophthalmol 64:33, 1980.

48. Travers JP, Patterson A: A controlled trial of adenine arabinoside and trifluorothymidine in herpetic keratitis. J Int Med Res 6:102, 1978.

49. Coster DJ, Jones BR, McGill JI: Treatment of amoeboid herpetic ulcers with adenine arabinoside or trifluorothymidine. Br J Ophthalmol 63:418, 1979.

50. Hyndiuk RA, Charlin RE, Alpren TVP et al: Trifluoridine in resistant human herpetic keratitis. Arch Ophthalmol 96:1839, 1978.

51. Falcon MG, Jones BR, Williams HP et al: Management of herpetic eye disease. Trans Ophthalmol Soc UK 97:345, 1977.

52. Wilhelmus KR, Coster DJ, Donovan HC et al: Prognostic indicators of herpetic keratitis: Analysis of a five-year observation period after corneal ulceration. Arch Ophthalmol 99:1578, 1981.

53. McNeil JI, Kaufman HE: Local antivirals in a herpes simplex stromal keratitis model. Arch Ophthalmol 97:727, 1979.

54. Wilhelmus KR, Gee L, Hauk WW et al: Herpetic Eye Disease Study. A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology 101:1883, 1994.

55. Little JM, Lorenzetti DWC, Brown DC et al: Studies of adenovirus type III infection treated with methisazone and trifluorothymidine. Proc Soc Exp Biol Med 127:1028, 1968.

55a. Cono J, Casey CG, Bell DM: Smallpox vaccination and adverse reactions. Guidance for clinicians. MMWR Recomm Rep 52(RR-4):1, 2003.

56. Lee WW, Benitez A, Goodman L et al: Potential anticancer agents: XL. Synthesis of the B-isomer of 9-($PI$vD-arabinofuranosyl)-adenine. J Am Chem Soc 82:2648, 1960.

57. Fiala M, Chow AW, Miyasaki K et al: Susceptibility of herpes viruses to three nucleoside analogues and their combinations and enhancement of the antiviral effect of acid pH. J Infect Dis 129:82, 1974.

58. Miller FA, Dixon GJ, Ehrlich J et al: Antiviral activity of 9-B-d arabinofuranashyladenine: Cell culture studies. In Hobby GI (ed): Antimicrobial Agents and Chemotherapy—1968, pp 136–147. Bethesda, American Society for Microbiology, 1969.

59. Nicholson KG: Properties of antiviral agents: First of two parts. Lancet 2:503, 1984.

60. Whitley R, Alford C, Hess F, Buchanan R: Vidarabine: A preliminary review of its pharmacological properties and therapeutic use. Drugs 20:267, 1980.

61. Erlich KS, Mills J, Chatis P et al: Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 320:293, 1989.

62. Hirsch MS, Schooley RT: Resistance to antiviral drugs: The end of innocence. N Engl J Med 320:313, 1989.

63. Larder BA, Darby Gusceptibility to other antiherpes drugs of pathogenic variants of herpes simplex virus selected for resistance to acyclovir. Antimicrob Agents Chemother 29:894, 1986.

64. Buchanan RA, Hess F: Vidarabine (Vira A) pharmacology and clinical experience. Pharmacol Ther 8:143, 1980.

65. Poirer RH, Kinkel AW, Ellison AC et al: Intraocular penetration of topical 3% adenine arabinoside. In Pavan-Langston D, Buchanon RA, Alford CA (eds): Adenine Arabinoside: An Antiviral Agent, pp. 313–321. New York, Raven Press, 1975.

66. Buchanan RA, Kinkel AW, Alford CA et al: Plasma levels and urinary excretion of vidarabine after repeated dosing. Clin Pharmacol Ther 27:690, 1980.

67. Abel R, Kaufman HE, Sugar J: Intravenous adenine arabinoside against herpes simplex keratouveitis in humans. Am J Ophthalmol 79:659, 1975.

68. Langston RHS, Pavan-Langston D, Dohlman CH: Antiviral medication and corneal wound healing. Arch Ophthalmol 92:509, 1974.

69. Ross AH, Julia A, Balakrishnan C: Toxicity of adenine arabinoside in humans. J Infect Dis 133:192, 1976.

70. Van Etta L, Brown J, Mastri A: Fatal vidarabine toxicity in a patient with normal renal function. JAMA 246:1703, 1981.

71. Gizzi M, Rudolph S, Perakis A: Ocular flutter in vidarabine toxicity. Am J Ophthalmol 109:105, 1990.

71a. Sachs SL, Scullard GH, Pollard RB et al: Antiviral treatment of chronic hepatitis B virus infectioPharmacokinetics and side effects of interferon and adenine arabinoside alone and in combination. Antimicrob Agents Chemother 21:73, 1982.

72. Friedman HM, Gransela T: Adenine arabinoside and allopurinol: Possible adverse drug reaction. N Engl J Med 304:423, 1981.

73. Schardein JL, Hentz DL, Petrere JA et al: The effect of vidarabine on the development of the offspring of rats, rabbits, and monkeys. Teratology 15:231, 1977.

74. Whitley RJ, Soong S-J, Dolin et al: Adenine arabinoside therapy of biopsy-proven herpes simplex encephalitis. N Engl J Med 297:289, 1977.

75. Whitley R, Hilty M, Haynes R et al: Vidarabine therapy of varicella in immunosuppressed patients. J Pediatr 101:125, 1982.

76. Whitley RJ, Soong S-J, Dolin R et al: Early vidarabine therapy to control the complications of herpes zoster in immunosuppressed patients. N Engl J Med 307:971, 1982.

76a. Whitley RJ, Gnann JW Jr, Hinthorn D et al: Disseminated herpes zoster in the immunocompromised host: A comparative trial of acyclovir and vidarabine. J Infect Dis 165:450, 1992.

77. Shepp DH, Dandliker PS, Meyers JD: Treatment of varicella-zoster virus infection in severely immunocompromised patients: A randomized comparison of acyclovir and vidarabine. N Engl J Med 314:208, 1986.

78. Skoldenberg B, Fosgren M, Alestig K et al: Acyclovir versus vidarabine in herpes simplex encephalitis: Randomized multicenter study in consecutive Swedish patients. Lancet 2:707, 1984.

79. Whitley RJ, Alford CA, Hirsch MS et al: Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med 314:144, 1986.

80. Whitley RJ, Arvin A, Prober C et al: A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. N Engl J Med 324:444, 1991.

81. Ch'ien LT, Cannon NJ, Whitley R et al: Effect of adenine arabinoside on cytomegalovirus infection. J Infect Dis 130:32, 1974.

82. Marker SC, Howard RJ, Groth KE et al: A trial of vidarabine for cytomegalovirus infection in renal transplant patients. Arch Intern Med 140:1441, 1980.

83. Rytel MW, Kauffman HM: Clinical efficacy of adenine arabinoside on cytomegalovirus infections in renal allograft recipients. J Infect Dis 133:202, 1976.

84. Laibson PR, Krachmer JH: Controlled comparison of adenine arabinoside and idoxuridine therapy of human superficial dendritic keratitis. In Pavan-Langston D, Buchanon RA, Alford CA Jr (eds): Adenine Arabinoside: An Antiviral AgenT, pp 323–330. New York, Raven Press, 1975.

85. Uninsky E, Jampol LM, Kaufman S et al: Disseminated herpes simplex infection with retinitis in a renal allograft recipient. Ophthalmology 90:175, 1983.

86. Pollard RB, Egbert PR, Gallagher JG et al: Cytomegalovirus retinitis in immunosuppressed hosts: I. Natural history and effects of treatment with adenine arabinoside. Ann Intern Med 93:655, 1980.

87. Moriyama K, Asano Y, Fujimoto K et al: Successful combination therapy with acyclovir and vidarabine for disseminated varicella zoster virus infection with retinal involvement in a patient with B-cell lymphoma and adult T-cell leukemia. Am J Med 85:885, 1988.

88. Dorsky DI, Crumpacker CS: Drugs five years later: Acyclovir. Ann Intern Med 107:859, 1987.

89. Wagstaff AJ, Faulds D, Goa KL: Aciclovir. A reappraisal of its antiviral activity, pharmacokinetic properties, and therapeutic efficacy. Drugs 47:153, 1994.

90. Griffiths PD, Emery VC: Cytomegalovirus. In Richman DD, Whitley RJ, Hayden FG (eds): Clinical Virology, pp 433–461. Washington, DC, ASM Press, 2002.

91. Schaeffer HJ: Acyclovir chemistry and spectrum of activity. Am J Med 73:4, 1982.

92. Elion GB, Furman PA, Fyfe JA et al: Selectivity of action of an antiherpetic agent 9-(2-hydroxyethoxymethyl) guanine. Proc Natl Acad Sci U S A 74:5716, 1977.

93. Elion GB: Mechanism of action and selectivity of acyclovir. Am J Med 73:7, 1982.

94. Furman PA, St Clair MH, Fyfe JA et al: Inhibition of herpes simplex virus induced DNA polymerase activity and viral DNA replication by 9-(2-hydroxyethoxymethyl) guanine and its triphosphate. J Virol 32:72, 1979.

95. Colby BM, Shaw JE, Elion GB et al: Effect of acyclovir [9-(2-hydroxyethoxymethyl) guanine] on Epstein-Barr virus DNA replication. J Virol 34:560, 1980.

96. Laskin OL: Acyclovir: Pharmacology and clinical experience. Ann Intern Med 144:1241, 1984.

97. Biron KK, Elion GB: In vitro susceptibility of varicellazoster virus to acyclovir. Antimicrob Agents Chemother 18:443, 1980.

98. Balfour HH Jr: Acyclovir. In Peterson PK, Verhoeft J (eds): Antimicrobial Agents Annual 3, p 345. Amsterdam, Elsevier Science, 1988.

99. DeMiranda P, Whitley RJ, Blum MR: Acyclovir kinetics after intravenous infusion. Clin Pharmacol Ther 26:718, 1979.

100. Whitley RJ, Blum MR, Barton N et al: Pharmacokinetics of acyclovir in humans following intravenous administration: A model for the development of parenteral antivirals. Am J Med 73:165, 1972.

101. Van Dyke RB, Connor JD, Wyborny C et al: Pharmacokinetics of orally administered acyclovir in patients with herpes progenitalis. Am J Med 73:172, 1982.

102. McKendrick MW, Case C, Burke C et al: Oral acyclovir in herpes zoster. J Antimicrob Chemother 14:661, 1984.

103. McKendrick MW, McGill JI, Bell HM et al: Oral acyclovir for herpes zoster. Lancet 2:925, 1984.

104. McKendrick MW, McGill JI, White JE et al: Oral acyclovir in acute herpes zoster. Br Med J 293:1529, 1986.

105. Collum LMT, Akhtar J, McGettrick P: Oral acyclovir in herpetic keratitis. Trans Ophthalmol Soc UK 104:629, 198.

106. Collum LMT, McGettrick P, Akhtar, et al: Oral acyclovir (Zovirax) in herpes simples dendritic corneal ulceration. Br J Ophthalmol 70:435, 1986.

107. Hung SO, Patterson A, Rees PJ: Pharmacokinetics of oral acyclovir (Zovirax) in the eye. Br J Ophthalmol 68:192, 1984.

108. Schulman JA, Peyman GA, Fiscella RG et al: Parentally administered acyclovir for viral retinitis associated with AIDSArch Ophthalmol 102:1750, 1984.

109. Schulman J, Peyman GA, Liu J et al: The intraocular penetration of acyclovir after subconjunctival administration. Ophthalmic Surg 18:111, 1987.

110. Grant DM: Acyclovir (Zovirax) ophthalmic ointment: A review of clinical tolerance. Curr Eye Res 6:231, 1987.

111. McCulley JP, Binder PS, Kaufman HE, at al: A double-blind, multicenter clinical trial of acyclovir vs idoxuridine for treatment of epithelial herpes simplex keratitis. Ophthalmology 89:1195, 1982.

112. Carney MD, Peyman GA, Goldberg MF et al: Acute retinal necrosis. Retina 6:85, 1986.

112a. Goldberg LH, Kaufman R, Kurtz TO et al: Continuous five-year treatment of patients with frequently recurring genital herpes simplex virus infection with acyclovir. J Med Virol 41:45, 1993.

113. Bean B, Aeppli D: Adverse effects of high-dose intravenous acyclovir in ambulatory patients with acute herpes zoster. J Infect Dis 151:362, 1985.

114. Keeney RE, Kirk LE, Bridgen D: Acyclovir tolerance in humans. Am J Med 73(1A):176, 1982.

115. Sylvester RK, Ogden WB, Draxler CA et al: Vesicular eruption: A local complication of concentrated acyclovir infusions. JAMA 255:385, 1986.

116. Balfour HH Jr: Acyclovir therapy for herpes zoster: Advantages and adverse effects. JAMA 255:387, 1986.

117. Bridgen D, Rosling AE, Woods NC: Renal function after acyclovir intravenous injection. Am J Med 73:182, 1982.

118. Eck P, Silver SM, Clark EC: Acute renal failure and coma after a high dose of oral acyclovir. N Engl J Med 325:1178, 1991.

119. Manka RL: Exogenous lactase in the treatment of oral acyclovir intolerance. Am J Ophthalmol 108:733, 1989.

120. Cohen SMZ, Minkove JA, Zebley JWIII et al: Severe but reversible neurotoxicity from acyclovir. Ann Intern Med 100:920, 1984.

121. Fletcher CV, Chinnock BJ, Chase B et al: Pharmacokinetics and safety of high dose oral acyclovir for suppression of cytomegalovirus disease after renal transplantation. Clin Pharmacol Ther 44:158, 1988.

122. Sirota P, Stoler M, Meshulam B: Major depression with psychotic features associated with acyclovir therapy. Drug Intell Clin Pharm 22:306, 1988.

123. Tomson CR, Goodiship THJ, Rodger RSC: Psychiatric side-effects of acyclovir in patients with chronic renal failure. Lancet 1:385, 1985.

124. Wade JC, Meyers JD: Neurologic symptoms associated with parenteral acyclovir treatment after bone marrow transplantation. Ann Intern Med 98:921, 1983.

125. Clive D, Turner NT, Hozier J et al: Preclinical toxicology studies with acyclovir: Genetic toxicity tests. Fundam Appl Toxicol 3:587, 1983.

126. Tucker WE Jr, Krasny HC, DeMiranda P et al: Preclinical toxicology studies with acyclovir. Carcinogenicity bioassays and chronic toxicity tests. Fundam Appl Toxicol 3:579, 1983.

127. Klug S, Lewandowski C, Blankenburg G et al: Effect of acyclovir on mammalian embryonic development in culture. Arch Toxicol 58:29, 1985.

128. Moore HL Jr, Szczech GM, Rodwell DE et al: Preclinical toxicology studies with acyclovir: Teratologic, reproductive and neonatal tests. Fundam Appl Toxicol 3:560, 1983.

129. Reiff-Eldridge R, Heffner CR, Ephross SA et al: Monitoring pregnancy outcomes after prenatal drug exposure through prospective pregnancy registries: A pharmaceutical company commitment. Am J Obstet Gynecol 182:159, 2000.

130. Greffe BS, Dooley SL, Deddish RB et al: Transplacental passage of acyclovir. J Pediatr 108:1020, 1986.

131. Brown ZA, Baker DA: Acyclovir therapy during pregnancy. Obstet Gynecol 73:526, 1989.

132. Van Landingham KE, Marsteller HB, Ross GW et al: Relapse of herpes simplex encephalitis after conventional acyclovir therapy. JAMA 259:1051, 1988.

133. Bryson YJ, Dillon M, Lovett M et al: Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir: A randomized double-blind controlled trial in normal subjects. N Engl J Med 308:916, 1983.

134. Corey L, Benedetti J, Critchlow C et al: Treatment of primary first-episode genital herpes simplex virus infections with acyclovir: Results of topical, intravenous, and oral therapy. J Antimicrob Chemother 12:79, 1983.

135. Mindel A, Adler MW, Sutherland S et al: Intravenous acyclovir treatment for primary genital herpes. Lancet 1:697, 1982.

136. Nilsen AE, Aasen T, Halsos AM et al: Efficacy of oral acyclovir treatment for primary genital herpes. Lancet 1:697, 1982.

137. Mertz GJ, Jones CC, Mills J: Long-term acyclovir suppression of frequently recurring genital herpes simplex virus infection. JAMA 260:201, 1988.

138. Spruance SL, Stewart JCB, Rowe NH et al: Treatment of recurrent herpes simplex labialis with oral acyclovir. J Infect Dis 161:185, 1990.

138a. Straus SE, Takiff HE, Mindell S et al: Suppression of frequently recurring genital herpes: A placebo-controlled double blind trial of oral acyclovir. N Engl J Med 310:1545, 1984.

139. Kaplowitz LG, Baker D, Gelb L et al: Prolonged continuous acyclovir treatment of normal adults with frequently recurring genital herpes simplex virus infection. JAMA 265:745, 1991.

140. Mertz GJ, Eron L, Kaufman R et al: Prolonged continuous versus intermittent oral acyclovir treatment in normal adults with frequently recurring genital herpes simplex virus infection. Am J Med 85:14, 1988.

140a. Spruance SL, Nett R, Marbury T et al: Acyclovir cream for the treatment of herpes simplex labialis: Results of two randomized double-blind vehicle-controlled multicenter clinical trials. Antimicrob Agents Chemother 46:2238, 2002.

140b. Amir J, Harel L, Smetana Z, Varsano I: Treatment of herpes simplex gingivostomatitis with acyclovir in children: a randomised double blind placebo controlled trial. BMJ 314:1800, 1997.

141. Gold D, Corey L: Acyclovir prophylaxis for herpes simplex virus infection. Antimicrob Agents Chemother 31:361, 1987.

142. Lundgren G, Wilczek H, Lonnquist B et al: Acyclovir prophylaxis in bone-marrow transplant recipients. Scand J Infect Dis 47:137, 1985.

143. Saral R, Ambinder RF, Burns WH et al: Acyclovir prophylaxis against herpes simplex virus infection in patients with leukemia. Ann Intern Med 99:773, 1983.

144. Saral R, Burns WH, Laskin OH et al: Acyclovir prophylaxis of herpes simplex virus infections: A randomized double-blind, controlled trial in bone-marrow transplant recipients. N Engl J Med 305:63, 1981.

145. Shepp DH, Newton B, Dandliker BS et al: Oral acyclovir therapy for mucocutaneous herpes simplex infections in immunocompromised marrow transplant recipients. Ann Intern Med 102:783, 1985.

146. Strauss SE, Seidlin M, Takiff H et al: Oral acyclovir to suppress recurrent herpes simplex virus infections in immunodeficient patients. Ann Intern Med 100:522, 1984.

147. Wade JC, Newton B, McLaren C et al: Intravenous acyclovir to treat mucocutaneous herpes simplex infection after marrow transplantation. Ann Intern Med 96:265, 1982.

148. Balfour HH, Bean B, Laskin OL et al: Acyclovir halts progression of herpes zoster in immunocompromised patients. N Engl J Med 308:1448, 1983.

149. Balfour HH Jr: Intravenous acyclovir therapy for varicella in immunocompromised children. J Pediatr 104:134, 1984.

150. Bean B, Brain C, Balfour HH Jr: Acyclovir therapy for acute herpes zoster. Lancet 2:118, 1982.

151. Feldman S, Lott L: Varicella in children with cancer: Impact of antiviral therapy and prophylaxis. Pediatrics 80:465, 1987.

152. Peterslund NA, Seyer-Hansen K, Ipsen J et al: Acyclovir in herpes zoster. Lancet 2:827, 1981.

153. Huff JC, Bean B, Balfour HH et al: Therapy of herpes zoster with oral acyclovir. Am J Med 85:84, 1988.

154. Buchi ER, Herbort CP, Ruffieux C: Oral acyclovir in the treatment of acute herpes zoster ophthalmicus. Am J Ophthalmol 102:531, 1986.

155. Cobo LM: Reduction of the ocular complications of herpes zoster ophthalmicus by oral acyclovir. Am J Med 85:90, 1988.

156. Cobo LM, Foulks GN, Liesegang T et al: Oral acyclovir in the therapy of acute herpes zoster ophthalmicus: An interim report. Ophthalmology 92:1574, 1985.

157. Cobo LM, Foulks GN, Liesegang T et al: Oral acyclovir in the treatment of acute herpes zoster ophthalmicus. Ophthalmology 93:763, 1986.

158. Wood MJ, Ogan PH, McKendrick MW et al: Efficacy of oral acyclovir treatment of acute herpes zoster. Am J Med 85:79, 1988.

158a. Wood MJ, Kay R, Dowrkin RH et al: Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: A meta-analysis of placebo-controlled trials. Clin Infect Dis 22:341, 1996.

158b. Gnann JW, Whitley RJ: Herpes Zoster. N Engl J Med 347:340, 2002.

159. Balfour HH Jr, Kelly JM, Suarez CS et al: Acyclovir treatment of varicella in otherwise healthy children. J Pediatr 116:633, 1990.

160. Dunkle LM, Arvin AM, Whitley RJ et al: A controlled trial of acyclovir for chickenpox in normal children. N Engl J Med 325:1539, 1991.

160a. Balfour HH Jr, Rotbart HA, Feldman S et al: Acyclovir treatment of varicella in otherwise healthy adolescents. J Pediatr 120:627, 1992.

161. Wallace MR, Bowler WA, Murray NB et al: Treatment of adult varicella with oral acyclovir: A randomized, placebo-controlled trialAnn Intern Med 117:358, 1992.

161a. American Academy of Pediatrics Committee on Infectious Diseases: The use of oral acyclovir in otherwise healthy children with varicella. Pediatrics 91:674, 1993.

161b. Cohen JI, Brunell PA, Strauss SE et al: Recent advances in varicella-zoster virus infection. Ann Intern Med 130:922, 1999.

162. Balfour HH Jr, Chace BA, Stapleton JT et al: A randomized placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N Engl J Med 320:1381, 1989.

163. Meyers JD, Reed EC, Shepp DH et al: Acyclovir for prevention of cytomegalovirus infection and disease after allogeneic marrow transplantation. N Engl J Med 318:70, 1988.

164. Balfour HH Jr, Bean B, Mitchell CD et al: Acyclovir in immunocompromised patients with cytomegalovirus disease. Am J Med 73:243, 1982.

165. Verheyden JPH: Evolution of the therapy for cytomegalovirus infection. Rev Infect Dis 10:S477, 1988.

166. Wade JC, Hintz M, McGuffin RW et al: Treatment of cytomegalovirus pneumonia with high dose acyclovir. Am J Med 73:249, 1982.

167. Plotkin SA, Starr SE, Bryan CK: In vitro and in vivo responses of cytomegalovirus to acyclovir. Am J Med 73:257, 1982.

168. Andersson J, Ernberg I: Management of Epstein-Barr virus infections. Am J Med 85:107, 1988.

169. van der Host C, Jonas J, Ahronheim G et al: Lack of effect of peroral acyclovir for the treatment of infectious mononucleosis. J Infect Dis 164:788, 1991.

170. Resnick L, Herbst JS, Ablashi DV et al: Regression of oral hairy leukoplakia after orally administered acyclovir therapy. JAMA 259:384, 1988.

171. Murakami S, Mizobuchi M, Nakashiro Y et al: Bell's palsy and herpes simplex virus: Identification of viral DNA in endoneural fluid and muscle. Ann Intern Med 124:27, 1996.

172. Adour KK, Ruboyianes JM, Von Doertsen PG et al: Bell's palsy treatment with acyclovir and prednisone compared with prednisone alone: A double-blind, randomized, controlled trial. Ann Otol Rhinol Laryngol 105:371, 1996.

172a. Grogan PM, Gronseth GS: Practice parameter: Steroids, acyclovir, and surgery for Bell's palsy (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56:830, 2001.

173. Coster DJ, Wilhelmus KR, Michael R et al: A comparison of acyclovir and idoxuridine as treatment for ulcerative herpetic keratitis. Br J Ophthalmol 64:763, 1980.

174. Collum LMT, Benedict-Smith A, Hillary IB: Randomised double-blind trial of acyclovir and idoxuridine in dendritic corneal ulceration. Br J Ophthalmol 64:766, 1980.

175. McGill J, Tormey P, Walter CB: Comparative trial of acyclovir and adenine arabinoside in the treatment of herpes simplex corneal ulcers. Br J Ophthalmol 65:610, 1981.

176. Young B, Patterson A, Ravenscroft T: A randomised double-blind clinical trial of acyclovir (Zovirax) and adenine arabinoside in herpes simplex corneal ulceration. Br J Ophthalmol 66:361, 1982.

177. Laibson PR, Pavan-Langston D, Yeakley WR et al: Acyclovir and vidarabine for the treatment of herpes simplex keratitis. Am J Med 73:281, 1982.

178. Collum LMT, Logan P, McAuliffe-Curtin D et al: Randomised double-blind trial of acyclovir (Zovirax) and adenine arabinoside in herpes simplex amoeboid corneal ulceration. Br J Ophthalmol 69:847, 1985.

179. La Lau C, Oosterhuis JA, Versteeg J et al: Acyclovir and trifluorothymidine in herpetic keratitis: A multicentre trial. Br J Ophthalmol 66:506, 1982.

180. Hovding G: A comparison between acyclovir and trifluorothymidine ophthalmic ointment in the treatment of epithelial dendritic keratitis: A double blind, randomized parallel group trial. Acta Ophthalmologica 67:51, 1989.

181. Hung SO, Patterson A, Clark D, Rees PJ: Oral acyclovir in the management of dendritic herpetic corneal ulceration. Br J Ophthalmol 68:398, 1984.

182. Schwab IR: Oral acyclovir in the management of herpes simplex ocular infections. Ophthalmology 95:423, 1988.

183. Gordon, YJ: The evolution of antiviral therapy for external ocular viral infections over twenty-five years. Cornea 19:673, 2000.

184. Margolis TP, Ostler HB: Treatment of ocular disease in eczema herpeticum. Am J Ophthalmol 110:274, 1990.

184a. Schwartz GS, Holland EJ: Oral acyclovir for the management of herpes simplex virus keratitis in children. Ophthalmology 107:278, 2000.

185. Beyer CF, Arens MQ, Hill GA et al: Oral acyclovir reduces the incidence of recurrent herpes simplex keratitis in rabbits after penetrating keratoplasty. Arch Ophthalmol 107:1200, 1989.

186. Green MT, Dunkel EC, Morris BL: Quantitation of herpes simplex virus type 1 shed in pre-ocular tear film of rabbits treated with acyclovir. Antimicrob Agents Chemother 20:580, 1981.

187. Pavan-Langston D, Park NH, Lass JH: Herpetic ganglionic latency: Acyclovir and vidarabine therapy. Arch Ophthalmol 97:1508, 1979.

188. Barney NP, Foster CS: A prospective randomized trial of oral acyclovir after penetrating keratoplasty for herpes simplex keratitis. Cornea 13:232, 1994.

189. Tambasco FP, Cohen EJ, Nguyen LH et al: Oral acyclovir after penetrating keratoplasty for herpes simplex. Arch Ophthalmol 117:445, 1999.

190. Simon AL, Pavan-Langston D: Long term oral acyclovir therapy: Effect on recurrent infectious herpes keratitis in patients with and without grafts. Ophthalmology 103:1399, 1996.

191. Wilhelmus KR: Diagnosis and management of herpes simplex stromal keratitis. Cornea 6:286, 1987.

192. Oh J: Enhancement of virus multiplication and interferon production by cortisone in ocular herpes virus infections. J Immunol 104:1359, 1970.

192a. Patterson A, Jones R: The management of ocular herpes. Trans Ophthalmol Soc UK 87:59, 1967.

193. Robbins RM, Galin MA: A model of steroid effects in herpes keratitis. Arch Ophthalmol 93:828, 1975.

194. Collum, LMT, Logan P, Ravenscroft T: Acyclovir (Zovirax) in herpetic disciform keratitis. Br J Ophthalmol 67:115, 1983.

195. VanGanswijk R, Oosterhuis JA, Swart-Van Den Berg M et al: Acyclovir treatment in stromal herpetic keratitis. Doc Ophthalmol 55:57, 1983.

196. Sanitato JJ, Asbell PA, Varnell ED et al: Acyclovir in the treatment of herpetic stromal disease. Am J Ophthalmol 98:537, 1984.

197. Barron BA, Gee L, Hauck WW et al: Herpetic Eye Disease Study. A controlled trial of oral acyclovir for herpes simplex stromal keratitis. Ophthalmology 101:1871, 1994.

198. The Herpetic Eye Disease Study Group: A controlled trial of oral acyclovir for the prevention of stromal keratitis or iritis in patients with herpes simplex virus epithelial keratitis. The epithelial keratitis trial. Arch Ophthalmol 115:703, 1997.

199. The Herpetic Eye Disease Study Group: A controlled trial of oral acyclovir for iridocyclitis caused by herpes simplex virus. Arch Ophthalmol 114:1065, 1996.

200. The Herpetic Eye Disease Study Group: Acyclovir for the prevention of recurrent herpes simplex virus eye disease. N Engl J Med 339:300, 1998.

201. The Herpetic Eye Disease Study Group: Oral acyclovir for herpes simplex virus eye disease. Effect on prevention of epithelial keratitis and stromal keratitis. Arch Ophthalmol 118:1030, 2000.

202. Grutzmacher RD, Henderson D, McDonald PJ et al: Herpes simplex chorioretinitis in a healthy adult. Am J Ophthalmol 96:788, 1983.

203. Nanda M, Curtin VT, Hilliard JK et al: Ocular histopathologic findings in a case of human herpes B virus infection. Arch Ophthalmol 108:713, 1990.

203a. Ragozzino MW, Melton LJIII , Chu CP et al: Population-based study of herpes zoster and its sequelae. Medicine 61:310, 1982.

204. McGill J: Topical acyclovir in herpes zoster ocular involvement. Br J Ophthalmol 65:542, 1981.

205. McGill J, Chapman C: A comparison of topical acyclovir with steroids in the treatment of herpes zoster keratouveitis. Br J Ophthalmol 76:746, 1983.

206. McGill J: The enigma of herpes stromal disease. Br J Ophthalmol 71:117, 1987.

207. Marsh RJ, Cooper M: Double-masked trial of topical acyclovir and steroids in the treatment of herpes zoster ocular inflammation. Br J Ophthalmol 75:542, 1991.

208. Zaal MJW, Maudgal PC, Rietveld E et al: Chronic ocular zoster. Curr Eye Res 10:125, 1991.

209. Engstrom RE, Holland GN: Chronic herpes zoster virus keratitis associated with the acquired immunodeficiency syndrome. Am J Ophthalmol 105:556, 1988.

209a. Chern KC, Conrad D, Holland GN et al: Chronic varicella-zoster virus epithelial keratitis in patients with acquired immunodeficiency syndrome. Arch Ophthalmol 116:1011–1017, 1998.

210. Harding SP, Porter SM: Oral acyclovir in herpes zoster ophthalmicus. Curr Eye Res 10:177, 1991.

211. Hoang-Xuan T, Büchi ER, Herbort CP et al: Oral acyclovir for herpes zoster ophthalmicus. Ophthalmology 99:1062, 1992.

212. Wood MJ, Johnson RW, McKendrick MW et al: A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med 330:896, 1994.

213. Wood MJ, Shukla S, Fiddian AP et al: Treatment of acute herpes zoster: Effect of early (<48h) versus late (48-72h) therapy with acyclovir and valaciclovir on prolonged pain. J Infect Dis 178:S81, 1998.

214. Aylward GW, Claove CM, Marsh RJ, Yaseem N: Influence of oral acyclovir on ocular complications of herpes zoster ophthalmicus. Eye 8:70, 1994.

215. Pepose JS: The potential impact of the varicella vaccine and new antivirals on ocular disease related to varicella-zoster virus. Am J Ophthalmol , 123:243, 1997.

216. Liesegang TJ: Varicella zoster viral disease. Mayo Clin Proc 74:983, 1999.

216a. Severson EA, Baratz KH, Hodge DO, Burke JP: Herpes zoster ophthalmicus in Olmsted County, Minnesota. Have systemic antivirals made a difference?Arch Ophthalmol 121:386, 2003.

217. Whitley RJ, Weiss H, Gnann JW et al: Acyclovir with or without prednisone for the treatment of herpes zoster. A randomized, placebo-controlled trialAnn Intern Med 125:376, 1996.

218. Harding SP, Lipton JR, Wells JCD: Natural history of herpes zoster ophthalmicus: Predictors of postherpetic neuralgia and ocular involvement. Br J Ophthalmol 81:353, 1987.

219. Alper BS, Peter RL: Does treatment of acute herpes zoster prevent or shorten postherpetic neuralgia? A systematic review of the literature. J Fam Prac 49:255, 2000.

220. Esmann V, Kroon S, Peterslund NA et al: Prednisolone does not prevent post-herpetic neuralgia. Lancet 2:126, 1987.

221. Colin J, Prisant O, Cochener B et al: Comparison of the efficacy and safety of valaciclovir and acyclovir for the treatment of herpes zoster ophthalmicus. Ophthalmology 107:1507, 2000

222. Buetner KR, Friedman DJ, Forszpaniak C et al: Valacyclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 39:1546, 1995.

223. Tyring S, Engst R, Corriveau C et al: Famciclovir for ophthalmic zoster: A randomized aciclovir controlled study. Br J Ophthalmol 85:576, 2001.

224. Balfour H: Varicella zoster virus infections in immunocompromised hosts: A review of the natural history and management. Am J Med 85:68, 1988.

225. Cole EL, Meisler DM, Calabrese LH et al: Herpes zoster ophthalmicus and acquired immunodeficiency syndrome. Arch Ophthalmol 102:1027, 1984.

226. Sandor EV, Millman A, Croxson TS et al: Herpes zoster ophthalmicus in patients at risk for the acquired immunodeficiency syndrome (AIDS). Am J Ophthalmol 101:153, 1986.

226a. Pepose JS, Biron K: Antiviral sensitivities of the acute retinal necrosis syndrome virus. Curr Eye Res 6:201, 1987.

227. Seiff SR, Margolis T, Oraham SH et al: Use of intravenous acyclovir for treatment of herpes zoster ophthalmicus in patients at risk for AIDS. Ann Ophthalmol 20:480, 1988.

228. Margolis TP, Milner MS, Shama A et al: Herpes zoster ophthalmicus in patients with human immunodeficiency virus infection. Am J Ophthalmol 125:285, 1998.

229. Jacobson MA, Berger TG, Fikrig S et al: Acyclovir-resistant varicella zoster virus infection after chronic oral acyclovir therapy in patients with acquired immunodeficiency syndrome (AIDS). Ann Intern Med 112:187, 1990.

230. Jabs DA, Schachat AP, Liss R et al: Presumed varicella zoster retinitis in immunocompromised patients. Retina 7:9, 1987.

231. Chess J, Marcus DM: Zoster-related bilateral acute retinal necrosis syndrome as presenting sign in AIDS. Ann Ophthalmol 20:431, 1988.

232. Forster DJ, Dugel PU, Fragieh GT et al: Rapidly progressive outer retinal necrosis in the acquired immunodeficiency syndrome. Am J Ophthalmol 110:341, 1990.

233. Margolis TP, Lowder CY, Holland GN: Varicella-zoster virus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 112:119, 1991.

233a. Sellitti TP, Huang AJW, Schiffman J et al: Association of herpes zoster ophthalmicus with acquired immunodeficiency syndrome and acute retinal necrosis. Am J Ophthalmol 116:297, 1993.

234. Duker JS, Blumenkranz MS: Diagnosis and management of the acute retinal necrosis (ARN) syndrome. Surv Ophthalmol 36:327, 1992.

235. Van Gelder RN, Willis JL, Holland GN, Kaplan HJ: Herpes simplex virus type 2 as a cause of acute retinal necrosis syndrome in young patients. Ophthalmology 108:869, 2001.

236. Pepose JS, Biron K: Antiviral sensitivities of the acute retinal necrosis syndrome virus. Curr Eye Res 6:201, 1987.

237. Blumenkranz MS, Culbertson WW, Clarkson JG et al: Treatment of the acute retinal necrosis syndrome with intravenous acyclovir. Ophthalmology 93:296, 1986.

238. Hirst L, Beyer TL, Waters D et al: Successful management of acute retinal necrosis with intravenous acyclovir. Arch Ophthalmol 19:445, 1987.

239. Matsuo T, Nakayama T, Koyama T et al: A proposed mild type of acute retinal necrosis syndrome. Am J Ophthalmol 105:579, 1988.

240. Crapotta JA, Freeman WR, Feldman RM et al: Visual outcome in acute retinal necrosis. Retina 13:208, 1993.

241. Palay DA, Sternberg P, Davis J et al: Decrease in the risk of bilateral acute retinal necrosis by acyclovir therapy. Am J Ophthalmol 112:250, 1991.

242. Matsuo T, Koyama M, Matsuo N: Acute retinal necrosis as a novel complication of chickenpox in adults. Br J Ophthalmol 74:443, 1990.

243. Astanides IM, DeSouza S, Wong DTW et al: Oral valacyclovir in the treatment of acute retinal necrosis syndrome. Retina 22:352, 2002.

244. Figueroa MS, Garabito I, Gutierrez C, Fortun J: Famciclovir for the treatment of acute retinal necrosis (ARN) syndrome. Am J Ophthalmol 123:255, 1997.

245. Klein JL, Sandy C, Migdal CS et al: Famciclovir in AIDS-related acute retinal necrosis. AIDS 10:1300, 1996.

246. Luu, KKM, Scott IV, Chaudhry NA et al: Intravitreal antiviral injections as adjunctive therapy in the management of immunocompetent patients with necrotizing herpetic retinopathy. Am J Ophthalmol 129:811, 2000.

247. Ando F, Kato M, Goto S et al: Platelet function in bilateral acute retinal necrosis. Am J Ophthalmol 96:22, 1983.

248. Peyman GA, Goldberg GF, Uninsky E, at al: Vitrectomy and intravitreal antiviral drug therapy in acute retinal necrosis syndrome: Report of two cases. Arch Ophthalmol 102:1617, 1984.

249. Engstrom RE, Holland GN, Margolis TP et al: The progressive outer retinal necrosis syndrome: A variant of necrotizing herpetic retinopathy in patients with AIDS. Ophthalmology 101:1488, 1994.

250. Spaide RF, Martin DF, Teich SA et al: Successful treatment of progressive outer retinal necrosis syndrome. Retina 16:479, 1996.

251. Moorthy RS, Weinberg DV, Teich SA et al: Management of varicella zoster virus retinitis in AIDS. Br J Ophthalmol 81:189, 1997.

252. Matoba AY: Ocular disease associated with Epstein-Barr virus infection. Surv Ophthalmol 35:145, 1990.

253. Wilhelmus KR: Ocular involvement in infectious mononucleosis. Am J Ophthalmol 91:117, 1981.

254. Matoba AY, Wilhelmus KR, Jones DB: Epstein-Barr viral stromal keratitis. Ophthalmology 93:746, 1986.

255. Pinnolis M, McCulley JP, Urman JD: Nummular keratitis associated with infectious mononucleosis. Am J Ophthalmol 89:791, 1980.

256. Pflugfelder SG, Huang A, Crouse C: Epstein-Barr virus keratitis after a chemical facial peel. Am J Ophthalmol 110:571, 1990.

257. Wong KW, D'Amico DJ, Hedges TRIII et al: Ocular involvement associated with chronic Epstein-Barr virus disease. Arch Ophthalmol 105:788, 1987.

258. Schooley RT, Carey RW, Miller G et al: Chronic Epstein-Barr virus infection associated with fever and interstitial pneumonitis: Clinical and serologic features and response to antiviral chemotherapy. Ann Intern Med 104:636, 1986.

259. Fay MT, Freeman WR, Wiley CA et al: Atypical retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 105:483, 1988.

260. Sha BE, Benson CA, Deutsch TA et al: Suppression of cytomegalovirus retinitis in persons with AIDS with high-dose intravenous acyclovir. J Infect Dis 164:777, 1991.

261. Fife KH, Crumpacker CS, Mertz GJ et al: Recurrence and resistance pattern of herpes simplex virus following cessation of >6 years of chronic suppression with acyclovir. J Infect Dis 169:1338, 1994.

262. Charles SJ, Gray JJ: Ocular herpes simplex virus infections: Reduced sensitivity to acyclovir in primary disease. Br J Ophthalmol 74:286, 1990.

263. Menage MJ, de Clerq E, van Lierde A et al: Antiviral drug sensitivity in ocular herpes simplex virus infection. Br J Ophthalmol 74:286, 1990.

264. Englund JA, Zimmerman ME, Swierkosz EM et al: Herpes simplex virus resistant to acyclovir: A study in a tertiary care center. Ann Intern Med 112:416, 1990.

265. Chatis PA, Miller CH, Schrager LE et al: Successful treatment with foscarnet of an acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with acquired immunodeficiency syndrome. N Engl J Med 320:297, 1989.

266. Kaplan MH, Sadick N, McNutt NS et al: Dermatologic findings and manifestations of acquired immunodeficiency syndrome (AIDS). J Am Acad Dermatol 16:485, 1987,

267. Marks GL, Nolan, PE, Erlich KS et al: Mucocutaneous dissemination of acyclovir-resistant herpes simplex virus in a patient with AIDS. Rev Infect Dis 11:474, 1989,

268. Field, HJ, Darby G: Pathogenecity in mice of strains of herpes simplex virus which are resistant to acyclovir in vitro and in vivo. Antimicrob Agents Chemother 17:209, 1980,

269. Safrin S, Assaykeen T, Follansbee S et al: Foscarnet therapy for acyclovir-resistant mucocutaneous herpes simplex virus infection in 26 AIDS patients: Preliminary data. J Infect Dis 161:1078, 1990,

270. Youle MM, Hawkins DA, Collins P et al: Acyclovir-resistant herpes in AIDS treated with foscarnet. Lancet 3:341, 1988.

271. Lalezari JP, Drew WL, Glutzer E et al: Treatment with intravenous (s)-1-[3-hydroxy-2-phosphonylmethoxy)propyl]-cytosine of acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with AIDS. J Infect Dis 170:570, 1994.

272. Engel JP, Englund JA, Fletcher CV et al: Treatment of resistant herpes simplex virus with continuous-infusion acyclovir. JAMA 263:1662, 1990.

273. Fletcher CV, Englund JA, Bean B et al: Continuous infusion of high dose acyclovir for serious herpes virus infections. Antimicrob Agents Chemother 33:1375, 1989.

274. Safrin S, Berger TG, Gilson I et al: Foscarnet therapy in five patients with AIDS and acyclovir-resistant varicella-zoster virus infection. Ann Intern Med 115:19, 1991.

275. Perry CM, Faulds D: Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpes virus infections. Drugs 52:755, 1996.

276. Acosta EP, Fletcher CV: Valacyclovir. Ann Pharmacother 31:185, 1997.

277. Ormrod D, Goa K: Valaciclovir. A review of its use in the management of herpes zoster. Drugs 59:1317, 2000.

278. Weller S, Blum MR, Doucette M et al: Pharmacokinetics of the acyclovir pro-drug, valacyclovir after escalating single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther 54:595, 1993.

279. Steingrimsdottir H, Gruber A, Palm C et al: Bioavailability of aciclovir after oral administration of aciclovir and its prodrug valaciclovir to patients with leukopenia after chemotherapy. Antimicrob Agents Chemother 44:207, 2000.

280. Ormrod D, Scott LJ, Perry CM: Valaciclovir. A review of its long term utility in the management of genital herpes simplex virus and cytomegalovirus infections. Drugs 59:839, 2000.

281. Soul-Lawton J, Seaber E, On N et al: Absolute bioavailability and metabolic disposition of valaciclovir, the $PI$vL-valyl ester of acyclovir following oral administration to humans. Antimicrob Agents Chemother 39:2759, 1995.

282. Jacobson MA, Gallant J, Wang LH et al: Phase 1 trial of valaciclovir, the $PI$vL-valyl ester of acyclovir, in patients with advanced human immunodeficiency virus disease. Antimicrob Agents Chemother 38:1534, 1994.

283. Decroix J, Partsch H, Gonzalez R et al: Factors influencing pain outcome in herpes zoster: An observational study with valaciclovir. J Eur Acad Dermatol Venereol 14:23, 2000.

284. Lowance D, Neumayer H-H, Legendre CM et al: Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. N Engl J Med 340:1462, 1999.

285. Feinberg JE, Hurwitz S, Cooper D et al: A randomized, double-blind trial of valaciclovir prophylaxis for cytomegalovirus disease in patients with advanced human immunodeficiency virus infection. J Infect Dis 177:48, 1998.

286. Izzedine H, Mercada IL, Aymard G et al: Neurotoxicity of valacyclovir in peritoneal dialysis: A pharmacokinetic study. Am J Nephrol 21:162, 2001.

287. Chulay JD, Bell AR: International Valaciclovir HSV Study Group: Long-term safety of valaciclovir for suppression of herpes simplex virus infections. Clin Infect Dis 23:879, 1996.

288. Fobelo MJ, Delgado JEC, Alonso AR et al: Aseptic meningitis related to valacyclovir. Ann Pharmacother 35:128, 2001.

289. Dekker, CL, Prober CG: Pediatric uses of valacyclovir, penciclovir and famciclovir. Pediatr Infect Dis J 20:1079, 2001.

290. Fife KH, Barbarash RA, Rudolph T et al: Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection. Results of an international multicenter double blind, randomized clinical trial. The Valaciclovir International Herpes Simplex Virus Study Group. Sex Transm Dis 24:481, 1997.

291. Tyring SK, Douglas JM Jr, Corey L et al: A randomized placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. The Valaciclovir International Study Group. Arch Dermatol 134:185, 1998.

292. Anonymous: Drugs for non-HIV viral infections. The Medical Letter44 :9, 2002.

293. Reitano M, Tyring S, Lang W et al: Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: A large scale dose range-finding study. J Infect Dis 1278:603, 1998.

294. Anonymous: Valacyclovir (Valtrex) for herpes labialis. The Medical Letter44:95, 2002.

295. Tyring SK, Buetner KR, Tucker BA et al: Antiviral therapy for herpes zoster. Randomized controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older. Arch Fam Med 9:863, 2000.

296. Leblanc RA, Pesnicak L, Godleski M et al: The comparative effects of famciclovir and valacyclovir on herpes simplex virus type 1 infection, latency, and reactivation in mice. J Infect Dis 180:594, 1999.

297. Harding SP, Rigal D, Easty DL et al: Superior intraocular penetration of aciclovir from valaciclovir in comparison with oral aciclovir. J Antimicrob Chemother 44:44, 1999.

298. Asbell PA: Valacyclovir for the prevention of recurrent herpes simplex virus eye disease after excimer laser photokeratectomy. Trans Am Ophthalmol Soc 98:285, 2000.

299. Dhalimal DK, Romanowski EG, Yates KA et al: Valacyclovir inhibition of ocular herpes simplex type 1 after experimental reactivation by laser in situ keratomileusis. J Cataract Refract Surg 27:1288, 2001.

300. Grant DM, Mauskopf JA, Bell L et al: Comparison of valaciclovir and acyclovir for the treatment of herpes zoster in immunocompetent patients over 50 years of age: A cost-consequence model. Pharmacotherapy 17:333, 1997.

301. Perry CM, Wagstaff AJ: Famciclovir. A review of its pharmacological properties and therapeutic efficacy in herpes virus infections. Drugs 50:396, 1995.

302. Pue MA, Benet LZ: Pharmacokinetics of famciclovir in man. Antiviral Chem Chemother 4:47, 1993.

302a. Boyd MR, Kern ER, Safrin S: Penciclovir: A review of its spectrum of activity, selectivity and cross-resistance pattern. Antivir Chem Chemother 4:3, 1993.

302b. Vere Hodge RA: Famciclovir and penciclovir: The mode of action of famciclovir including its conversion to penciclovir. Antivir Chem Chemother 4:67, 1993.

303. Degreef H,: The Famciclvir Herpes Zoster Clinical Study Group: Famciclovir, a new oral antiherpes drug: Results of the first controlled clinical study demonstrating its efficacy and safety in the treatment of uncomplicated herpes zoster in immunocompetent patients. Int J Antimicrob Agents 4:241, 1994.

304. Saltzman R, Jurewicz R, Boon R: Safety of famciclovir in patients with herpes zoster and genital herpes. Antimicrob Agents Chemother 38:2454, 1994.

305. Loveless M, Sacks SL, Harris RJ: Famciclovir in the management of first-episode genital herpes. Infect Dis Clin Pract 6:S12, 1997.

305a. Sacks SL, Aoki FY, Diaz-Mitoma F et al: Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. A randomized, double-blind multicenter trial. Canadian Famciclovir Study Group. JAMA 276:44, 1996.

305b. Mertz GJ, Loveless MO, Levin MJ et al: Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial. Collaborative Famciclovir Genital Herpes Research Group. Arch Intern Med 157:343, 1997.

306. Tyring S, Barbarash RA, Nahlik JE et al: Famciclovir for the treatment of acute herpes zoster: Effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Collaborative Famciclovir Herpes Zoster Study Group. Ann Intern Med 123:89, 1995.

307. Dworkin RH, Boon RJ, Griffin DRJ, Phung D: Postherpetic neuralgia: impact of famciclovir, age, rash, severity, and acute pain in herpes zoster patients. J Infect Dis 178:S76, 1998.

308. Spruance RL, Rea TL, Thoming C et al: Penciclovir cream for the treatment of herpes simplex labialis. A randomized, multicenter, double-blind, placebo-controlled trial. JAMA 277:1374, 1997.

309. Kaufman HE, Varnell ED, Thompson HW: Trifluridine, cidofovir, and penciclovir in the treatment of experimental herpetic keratitis. Arch Ophthalmol 116:777, 1998.

310. Loutsch JM, Sainz B Jr, Marquart ME et al: Effect of famciclovir on herpes simplex virus type 1 corneal disease and establishment of latency in rabbits. Antimicrob Agents Chemother 45:2044, 2001.

311. Spruance SL, Rowe NH, Raborn GW et al: Peroral famciclovir in the treatment of experimental ultraviolet radiation-induced herpes simplex labialis: A double blind, dose-ranging, placebo-controlled, multicenter trial. J Infect Dis 179:303, 1999.

312. Diaz-Mitoma F, Sibbald RG, Shafran SD et al: Oral famciclovir for the suppression of recurrent genital herpes: A randomized controlled trial. JAMA 280:887, 1998.

313. Cole NL, Balfour HH: In vitro susceptibility of cytomegalovirus isolates from immunosuppressed patients to acyclovir and ganciclovir. Diagn Microbiol Infect Dis 6:255, 1987.

314. Mar E-C, Cheng Y-C, Huang E-S: Effect of 9-(1$PI$XC3 dihydroxy-2-propoxymethyl) guanine on human cytomegalovirus replication in vivo. Antimicrob Agents Chemother 24:518, 1983.

315. Matthews T, Boehme R: Antiviral activity and mechanism of action of ganciclovir. Rev Infect Dis 10:S490, 1988.

316. Smee DF, Martin JC, Verheyden JPH et al: Anti-herpesvirus activity of the acyclic nucleoside 9-(1$PI$XC3-dihydroxy-2-propoxymethyl) guanine. Antimicrob Agents Chemother 23:676, 1983.

317. Tocci MJ, Livelli TJ, Perry HC et al: Effects of the nucleoside analog 2'-nor-2'-deoxyguanosine on human cytomegalovirus replication. Antimicrob Agents Chemother 25:247, 1984.

318. Crumpacker CS: Ganciclovir. N Engl J Med 355:721, 1996.

319. Noble S, Faulds D: Ganciclovir. An update of its use in the prevention of cytomegalovirus infection and disease in transplant recipients. Drugs 56:115, 1998.

320. Mar E-C, Chiou J-F, Cheng Y-C et al: Inhibition of cellular DNA polymerase alpha and human cytomegalovirus-induced DNA polymerase by the triphosphate of 9-(2-hydroxyethoxymethyl) guanine and 9-(1$PI$XC3-dihydroxy-2-propoxymethyl) guanine. J Virol 53:776, 1985.

321. Jacobson MA, DeMiranda P, Cederberg DM et al: Human pharmacokinetics and tolerance of oral ganciclovir. Antimicrob Agents Chemother 31:1251, 1987.

322. Anderson RD, Griffey KG, Jung D et al: Ganciclovir absolute bioavailability and steady-state pharmacokinetics after oral administration of two 3,000 mg/d dosing regimens in human immunodeficiency virus- and cytomegalovirus-seropositive patients. Clin Ther 17:425, 1995.

323. Lalezari JP, Friedberg DN, Bisset J et al: High dose oral ganciclovir treatment for cytomegalovirus retinitis. J Clin Virol 24:67, 2002.

324. Spector SA, Busch DF, Follansbee S et al: Pharmacokinetics, safety, and antiviral profiles of oral ganciclovir in persons infected with human immunodeficiency virus: A phase I/II study. J Infect Dis 171:1431, 1995.

325. Jacobson MA: Ganciclovir therapy for opportunistic cytomegalovirus disease in AIDS. In Volberding P, Jacobson MA (eds): AIDS Clinical Review 1990. New York, Marcel Dekker, 1990.

326. Laskin OL, Stahl-Bayliss CM, Kalman CM et al: Use of ganciclovir to treat serious cytomegalovirus infections in patients with AIDS. J Infect Dis 155:323, 1987.

327. Plotkin SA, Drew WL, Felsenstein D et al: Sensitivity of clinical isolates of human cytomegalovirus to 9-(1$PI$XC3-dihydroxy-2-propoxymethyl) guanine. J Infect Dis 152:833, 1985.

328. Sommadossi JP, Bevan R, Ling T et al: Clinical pharmacokinetics of ganciclovir in patients with normal and impaired renal function. Rev Infect Dis 10:S507, 1988,

329. Jabs DA, Wingard JR, deBustros S et al: BW B759U for cytomegalovirus retinitis: Intraocular drug penetration. Arch Ophthalmol 107:1436, 1986.

330. Arevalo JF, Gonzalez C, Capparelli EV et al: Intravitreous and plasma concentrations of ganciclovir and foscarnet after intravenous therapy in patients with AIDS and cytomegalovirus retinitis. J Infect Dis 172:951, 1995.

331. Buhles WC Jr, Mastre BJ, Tinker AJ et al: Ganciclovir treatment of life or sight-threatening cytomegalovirus infection: Experience in 314 immunocompromised patients. Rev Infect Dis 10:S495, 1988.

332. Davis CL, Springmeyer S, Gmerek BJ: Central nervous system side effects of ganciclovir. N Engl J Med 322:933, 1990.

333. Shea BF, Hoffman S, Sesin GP et al: Ganciclovir hepatotoxicity. Pharmacotherapy 1545:223, 1987.

334. Dennehy PJ, Warman R, Flynn JT et al: Ocular manifestations in pediatric patients with acquired immunodeficiency syndrome. Arch Ophthalmol 107:978, 1989.

335. Gudnason T, Belani KK, Balfour HH Jr: Ganciclovir treatment of cytomegalovirus disease in immunocompromised children. Pediatr Infect Dis J 8:436, 1989.

336. Markham A, Faulds D: Ganciclovir. An update of its therapeutic use in cytomegalovirus infection. Drugs 48:455, 1994.

337. Erice A: Resistance of human cytomegalovirus to antiviral drugs. Clin Microbiol Rev 12:286, 1999.

338. Smith IL, Cherrington JM, Jiles RE et al: High-level resistance of cytomegalovirus to ganciclovir is associated with alterations in both the UL97 and DNA polymerase genes. J Infect Dis 178:1821, 1998.

339. Dieterich DT, Kotler DP, Busch DF et al: Ganciclovir treatment of cytomegalovirus colitis in AIDS: A randomized, double-blind, placebo-controlled multicenter study. J Infect Dis 167:278, 1993

340. Lastin OL, Cederberg DM, Mills J et al: Ganciclovir for the treatment and suppression of serious infections caused by cytomegalovirus. Am J Med 83:201, 1987.

341. Fiala M, Cone LA, Cohen, et al: Response to neurologic complications of AIDS to 3'-azido-3'-deoxythymidine and 9-(1$PI$XC3-dihydroxy-2-propoxymethyl) guanine: I. Clinical features. Rev Infect Dis 10:250, 1988.

342. Merigan TC, Renlund DG, Keay S et al: A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation. N Engl J Med 326:1182, 1992.

343. Goodrich JM, Mori M, Gleaves CA et al: Early treatment with ganciclovir to prevent cytomegalovirus disease after allogenic bone marrow transplantation. N Engl J Med 325:1601, 1991.

344. Schmidt GM, Horak DA, Niland JC et al: A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants. N Engl J Med 324:1005, 1991.

345. Shepp DH, Dandliker PS, deMiranda P et al: Activity of 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl] guanine in the treatment of cytomegalovirus pneumonia. Ann Intern Med 103:368, 1985.

346. Reed EC, Dandliker PS, Meyers JD: Treatment of cytomegalovirus pneumonia with 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl] guanine and high dose corticosteroids. Ann Intern Med 105:214, 1986.

347. Emanuel DI, Cunningham K, Jules-Elysee K et al: Cytomegalovirus pneumonia after bone-marrow transplantation successfully treated with the combination of ganciclovir and high dose intravenous immune globulin. Ann Intern Med 109:777, 1988.

348. Schmidt GM, Forman SJ, Zaia JA et al: Treatment of cytomegalovirus associated pneumonitis with ganciclovir (DHPG) and immunoglobulin following allogeneic bone marrow transplantation: Antiviral and therapeutic response. Clin Res 36:470A, 1988.

349. Reed EC, Bowden RA, Dandliker PS et al: Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med 109:783, 1988.

350. Erice A, Jordan C, Chace BA et al: Ganciclovir treatment of cytomegalovirus disease in transplant recipients and other immunocompromised hosts. JAMA 257:3082, 1987.

351. Hecht DW, Snydman DR, Crumpacker CS et al: Ganciclovir for treatment of renal transplant-associated primary cytomegalovirus pneumonia. J Infect Dis 157:187, 1988.

352. Keay S, Bissett J, Merigan TC: Ganciclovir treatment of cytomegalovirus infection in iatrogenically immunocompromised patients. J Infect Dis 156:1016, 1987.

353. Couchoud C: Cytomegalovirus prophylaxis with antiviral agents for solid organ transplantation. Cochrane Database Syst Rev CD001320, 2000.

354. Gourishankar S, Wong W, Dorval M: Meta-analysis of prophylaxis of CMV disease in solid organ transplantation: is Ganciclovir a superior agent to Acyclovir?Transplant Proc 33:1870, 2001.

354a. Koetz AC, Delbruch R, Meyer-Koenig U et al: CMV pp 65 antigen guided preemptive ganciclovir therapy in solid transplant recipients: A prospective, double-blind and placebo-controlled study. Transplantation 72:1325, 2001.

355. Muheim C, Vogel G, Seydoux C et al: Determinants of protracted cytomegalovirus infection in solid-organ transplant patients. Transplantation 74:226, 2002.

355a. Badley AD, Seaberg EC, Porayko MK et al: Prophylaxis of cytomegalovirus infection in liver transplantation: a randomized trial comparing a combination of ganciclovir and acyclovir to acyclovir. NIDDK Liver transplantation Database. Transplantation 64:55, 1997.

355b. Grennan DC, Garlock KA, Singer GG et al: Prophylactic oral ganciclovir compared with deferred therapy for control of cytomegalovirus in renal transplant recipients. Transplantation 64:1843, 1997.

355c. Rubin RH, Kemmerly SA, Conti D et al: Prevention of primary cytomegalovirus disease in organ transplant recipients with oral ganciclovir or oral acyclovir prophylaxis. Transpl Infect Dis 2:112, 2000.

356. Shuman JS, Orellana J, Friedman AH et al: Acquired immunodeficiency syndrome (AIDS). Surv Ophthalmol 31:384, 1987.

357. Jabs DA: Ocular manifestations of HIV infection. Trans Am Ophthalmol Soc 93:623, 1995.

358. Hoover DR, Peng Y, Saah A et al: Occurrence of cytomegalovirus retinitis after human immunodeficiency virus immunosuppression. Arch Ophthalmol 114:821, 1996.

359. Jabs DA, Enger C, Bartlett JG: Cytomegalovirus retinitis and acquired immunodeficiency syndrome. Arch Ophthalmol 107:75, 1989.

360. Sison RF, Holland GN, MacArthur LJ et al: Cytomegalovirus retinopathy as the initial manifestation of the acquired immunodeficiency syndrome. Am J Ophthalmol 112:243, 1991.

361. Spector SA, McKinley C, Lalezari JP et al: Oval ganciclovir for the prevention of cytomegalovirus disease in persons with AIDS. N Engl J Med 334:1491, 1996.

362. Henderly DE, Freeman WR, Causey DM et al: Cytomegalovirus retinitis and response to therapy with ganciclovir. Ophthalmology 94:425, 1987.

363. Holland GN, Sidikaro Y, Kreiger EA et al: Treatment of cytomegalovirus retinopathy with ganciclovir. Ophthalmology 94:815, 1987.

364. Masur H, Lane HC, Palestine A et al: Effect of 9(1$PI$XC3 dihydroxy-2-propoxymethyl) guanine on serious cytomegalovirus disease in eight immunosuppressed homosexual men. Ann Intern Med 104:41, 1986.

365. Orellana J, Teich SA, Friedman AH et al: Combined short- and long-term therapy of cytomegalovirus retinitis using ganciclovir (BWB759U). Ophthalmology 94:831, 1987.

366. Palestine AG, Stevens G, Lane HC et al: Treatment of cytomegalovirus retinitis with dihydroxy propoxymethyl guanine. Am J Ophthalmol 101:95, 1986.

367. Rosecan LR, Stahl-Bayliss CM, Kalman CM et al: Antiviral therapy for cytomegalovirus retinitis in AIDS with dihydroxy propoxymethyl guanine. Am J Ophthalmol 101:405, 1986.

368. Holland GN, Buhles WC Jr, Mastre B et al: A controlled retrospective study of ganciclovir treatment for cytomegalovirus retinopathy: Use of a standardized system for the assessment of disease outcome. Arch Ophthalmol 107:1759, 1989.

368a. Spector SA, Weingeist T, Pollard RB et al: A randomized, controlled study of intravenous ganciclovir therapy for cytomegalovirus retinitis in patients with AIDS. AIDS Clinical Trials Group and Cytomegalovirus Cooperative Study Group. J Infect Dis 168:447, 1993.

369. Gross JG, Bozzette SA, Mathews WC et al: Longitudinal study of cytomegalovirus retinitis in acquired immune deficiency syndrome. Ophthalmology 97:681, 1990.

370. Studies of the Ocular Complications of AIDS Research Group, in collaboration with the AIDS Clinical Trials Group: Foscarnet-ganciclovir cytomegalovirus retinitis trial 4: Visual outcomes. Ophthalmology 101:1250, 1994.

371. Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group: Clinical vs photographic assessment of cytomegalovirus retinitis. Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial Report 8. Arch Ophthalmol 144:848, 1996.

372. D'Amico DJ, Talamo JH, Feldstein D et al: Ophthalmoscopic and histologic findings in cytomegalovirus retinitis treated with BW-B759U. Arch Ophthalmol 104:1788, 1986.

373. Pepose JS, Newman C, Bach MC et al: Pathologic features of cytomegalovirus retinopathy after treatment with the antiviral agent ganciclovir. Ophthalmology 94:414, 1987.

374. Teich SA, Castle J, Friedman AH et al: Active cytomegalovirus particles in the eyes of an AIDS patient being treated with 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl] guanine (ganciclovir). Br J Ophthalmol 72:293, 1988.

375. Jacobson MA, O'Donnell JJ, Brodie HR et al: Randomized prospective trial of ganciclovir maintenance therapy for cytomegalovirus retinitis. J Med Virol 25:339, 1988.

375a. Kupperman BD, Quiceno JI, Flores-Aguilar M et al: Intravitreal ganciclovir concentration after intravenous administration in AIDS patients with cytomegalovirus retinitis: Implications for therapy. J Infect Dis 168:1506, 1993.

376. Drew WL, Miner RC, Bush DF et al: Prevalence of resistance in patients receiving ganciclovir for serious cytomegalovirus infection. J Infect Dis 163:716, 1991.

377. Jabs DA, Enger C, Dunn JP et al for the Cytomegalovirus Retinitis and Viral Resistance Study Group: Cytomegalovirus resistance and viral resistance: 4. Ganciclovir resistance. J Infect Dis 177:770, 1998.

378. Jabs DA, Martin BK, Forman MS et al: Cytomegalovirus resistance to ganciclovir and clinical outcomes of patients with cytomegalovirus retinitis. Am J Ophthalmol 135:26, 2003.

379. The Studies of Ocular Complications of AIDS (SOCA) Research Group in collaboration with the AIDS Clinical Trials Group (ACTG): Rhegmatogenous retinal detachment in patients with cytomegalovirus retinitis: The Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial. Am J Ophthalmol 124:61, 1997.

380. Kempen JH, Jabs DA, Dunn JP et al: Retinal detachment risk in cytomegalovirus retinitis related to the acquired immune deficiency syndrome. Arch Ophthalmol 119:33, 2001.

381. Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group: Morbidity and toxic effects associated with ganciclovir or foscarnet in a randomized cytomegalovirus retinitis trial. Arch Intern Med 155:65, 1995.

382. Michael D, Min Y-I, Holbrook JT et al: Use of filgrastim as adjuvant therapy in patients with AIDS-related cytomegalovirus retinitis. AIDS 16:757, 2002.

382a. Studies of the Ocular Complications of AIDS (SOCA) Research Group in Collaboration with the AIDS Clinical Trials Group: Combination foscarnet and ganciclovir therapy vs. monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. Arch Ophthalmol 114:23, 1996.

383. Stanley HD, Charlebois E, Harb G et al: Central venous catheter infections in AIDS patients receiving treatment for cytomegalovirus disease. J Acquir Immune Defic Syndrome 7:272, 1994.

384. Drew WL, Ives D, Lalezari JP et al: Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. N Engl J Med 333:615, 1995.

385. The Oral Ganciclovir European and Australian Cooperative Study Group: Intravenous versus oral ganciclovir: European/Australian comparative study of efficacy and safety in the prevention of cytomegalovirus retinitis recurrence in patients with AIDS. AIDS 9:471, 1995.

386. Holland GN, Tufail A: New therapies for cytomegalovirus retinitis. N Engl J Med 333:658, 1995.

387. Martin DF, Kuppermann BD, Wolitz RA et al: Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. N Engl J Med 340:1063, 1999

388. Brosgart CL, Louis TA, Hillman DW et al: A randomized, placebo-controlled trial of the safety and efficacy of oral ganciclovir for prophylaxis of cytomegalovirus disease in HIV-infected individuals. AIDS 12:269, 1998.

389. Cheung TW, Teich SA: Cytomegalovirus infection in patients with HIV infection. Mount Sinai J Med 66:113, 1999.

390. Spector SA, Wong R, Hsia K et al: Plasma cytomegalovirus DNA load predicts CMV disease and survival in AIDS patients. J Clin Invest 101:497, 1998.

391. CDC: Guidelines for preventing opportunistic infections among HIV-infected persons—2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR Morb Mortal Wkly Rep 51(No. RR-8):1, 2002.

392. Smith TJ, Pearson PA, Blandford DL et al: Intravitreal sustained-release ganciclovir. Arch Ophthalmol 110:255, 1992.

392a. Musch DC, Martin DF, Gordon JF et al: Treatment of AIDS related CMV retinitis with a sustained-release ganciclovir implant. N Engl J Med 337:83, 1997.

392b. Martin DF, Parks DJ, Mellow SD et al: Treatment of cytomegalovirus retinitis with an intraocular sustained-release ganciclovir implant. A randomized controlled clinical trial. Arch Ophthalmol 112:1531, 1994.

393. Martin DF, Dunn JP, Davis JL et al: Use of the ganciclovir implant for the treatment of cytomegalovirus retinitis in the era of potent antiretroviral therapy: recommendations of the international AIDS society—USA Panel. Am J Ophthalmol 127:329, 1999.

394. Perkins SL, Chang-Hao Y, Ashton PA et al: Pharmacokinetics of the ganciclovir implant in the silicone-filled eye. Retina 21:10, 2001.

395. Martidis A, Danis RP, Ciulla TA: Treating cytomegalovirus retinitis-related retinal detachment by combining silicone oil tamponade and ganciclovir implant. Ophthalmic Surg Lasers 33:135, 2002

396. Kuo IC, Imoi Y, Shum C et al: Genotypic analysis of cytomegalovirus retinitis poorly responsive to intravenous ganciclovir but responsive to the ganciclovir implant. Am J Ophthalmol 135:20, 2003.

397. Marx JL, Kapusta MA, Patel SS et al: Use of the ganciclovir implant in the treatment of recurrent cytomegalovirus retinitis. Arch Ophthalmol 114:815, 1996.

398. Roth DB, Fever WJ, Blenke AJ et al: Treatment of recurrent cytomegalovirus retinitis with the ganciclovir implant. Am J Ophthalmol 127:276, 1999.

399. Hatton MP, Duker JS, Reichel E et al: Treatment of relapsed cytomegalovirus retinitis with the sustained-release ganciclovir implant. Retina 18:50, 1998.

400. Davis JL, Homayoun T, Feuer WJ et al: Effect of potent antiretroviral therapy on recurrent cytomegalovirus retinitis treated with the ganciclovir implant. Am J Ophthalmol 127:283, 1999.

401. Lim JI, Wolitz RA, Dowling AH et al: Visual and anatomic outcomes associated with posterior segment complications after ganciclovir implant procedures in patients with AIDS and cytomegalovirus retinitis. Am J Ophthalmol 127:288, 1999.

402. Guembol HO, Krieglsteiner S, Rosencranz C et al: Complications after implantation of intraocular devices in patients with cytomegalovirus retinitis. Graefes Arch Clin Exp Ophthalmol 237:824, 1999.

403. Charles NC, Freisberg L: Endophthalmitis associated with extrusion of a ganciclovir implant. Am J Ophthalmol 133:273, 2002.

404. Gentile RC, Lewis JM, Puklin JE: Cyclodialysis complicating intravitreal ganciclovir implantation. Arch Ophthalmol 115:1204, 1997.

405. Martin DF, Ferris FL, Brothers RJ et al: Retinal detachment in eyes treated with a ganciclovir implant. Arch Ophthalmol 113:1355, 1995.

406. The Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group: The ganciclovir implant plus oral ganciclovir versus parenteral cidofovir for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome: the Ganciclovir Cidofovir Cytomegalovirus Retinitis Trial. Am J Ophthalmol 131:457, 2001.

407. Pepose JS, Holland GN, Nestor MS et al: Acquired immune deficiency syndrome: Pathogenic mechanisms of ocular disease. Ophthalmology 92:472, 1985.

408. Palestine AG, Rodrigues MM, Macher AM et al: Ophthalmic involvement in acquired immune deficiency syndrome. Ophthalmology 91:1092, 1984.

409. Skolnick PR, Pomerantz RJ, de al Monte SM et al: Dual infection of retina with human immunodeficiency virus type I and cytomegalovirus. Am J Ophthalmol 107:361, 1989.

410. Holland GN, Sison RF, Jatulis DE et al: Survival of patients with the acquired immune deficiency syndrome after development of cytomegalovirus retinopathy. Ophthalmology 92:204, 1990.

411. Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group: Mortality in patients with the acquired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis. N Engl J Med 326:213, 1992.

412. Studies of the Ocular Complications of AIDS Research Group in collaboration with AIDS Clinical Trials Group: Antiviral effects of foscarnet and ganciclovir therapy on human immunodeficiency virus p24 antigen in patients with AIDS and cytomegalovirus retinitis. J Infect Dis 172:613, 1995.

413. Henry K, Cantrill H, Fletcher C et al: Use of intravitreal ganciclovir for CMV retinitis in a patient with AIDS. Am J Ophthalmol 103:17, 1987.

414. Cantrill HL, Henry K, Melroe NH et al: Treatment of cytomegalovirus retinitis with intravitreal ganciclovir: Long-term results. Ophthalmology 96:367, 1989.

415. Heinemann M-H: Staphylococcus epidermidis endophthalmitis complicating intravitreal antiviral therapy for cytomegalovirus retinitis. Arch Ophthalmol 107:643, 1989.

416. Heinemann MH: Long-term intravitreal ganciclovir therapy for cytomegalovirus retinopathy. Arch Ophthalmol 107:1767, 1989.

417. Ussery F, Gibson S, Conklin R et al: Intravitreal ganciclovir in the treatment of AIDS associated with cytomegalovirus retinitis. Ophthalmology 95:640, 1988.

418. Hodge WG, LaLonde RG, Sampalis J et al: Once weekly intraocular injection of ganciclovir for maintenance therapy of cytomegalovirus retinitis: Clinical and ocular outcome. J Infect Dis 174:393, 1996.

419. Yoshizumi MO, Lee D, Vinci V et al: Ocular toxicity of multiple intravitreal DHPG injections. Graefes Arch Clin Exp Ophthalmol 228:350, 1990.

420. Cochereau-Massin I, LeHoang P, Lautier-Frau M et al: Efficacy and tolerance of intravitreal ganciclovir in cytomegalovirus retinitis in acquired immune deficiency syndrome. Ophthalmology 98:1348, 1991.

421. Young SH, Morlet N, Heery S et al: High dose intravitreal ganciclovir in the treatment of cytomegalovirus retinitis. Med J Aust 157:370, 1992.

422. Young S, Morlet N, Besen G et al: High dose (2$PI$XC000-microgram) intravitreous ganciclovir in the treatment of cytomegalovirus retinitis. Ophthalmology 105:404, 1998.

423. Morlet N, Young S, Naidoo D et al: High dose intravitreal ganciclovir injection provides a prolonged therapeutic intraocular concentration. Br J Ophthalmol 80:214, 1996.

424. Desatnick HR, Foster RE, Lowder CY: Treatment of clinically resistant cytomegalovirus retinitis with combined intravitreal injections of ganciclovir and foscarnet. Am J Ophthalmol 122:121, 1996.

425. Velez G, Roy CE, Whitcup SM et al: High-dose intravitreal ganciclovir and foscarnet for cytomegalovirus retinitis. Am J Ophthalmol 131:396, 2001.

426. Saran BR, Maguire AM: Retinal toxicity of high dose intravitreal ganciclovir. Retina 14:248, 1994.

427. Hoh, HB, Hurley C, Claoue C et al: Randomised trial of ganciclovir and acyclovir in the treatment of herpes simplex dendritic keratitis: A multicentre study. Br J Ophthalmol 80:140, 1996.

428. Colin J, Hoh HB, Easty DL et al: Ganciclovir ophthalmic gel (Virgan; 0.15%) in the treatment of herpes simplex keratitis. Cornea 16:393, 1997.

429. Curran M, Noble S: Valganciclovir. Drugs 61:1145, 2001.

430. Jung D, Dorr A: Single dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects. J Clin Pharmacol 39:800, 1999.

431. Martin DF, Sierra-Madero J, Walmsley S et al: A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 346:1119, 2002.

432. Brown F, Banken L, Saywell K, Arum I: Pharmacokinetics of valganciclovir and ganciclovir following multiple oral doses of valganciclovir in HIV- and CMV-seropositive volunteers. Clin Pharmacokinet 37:167, 1999.

433. Segarra-Newnham M, Salazar MI: Valganciclovir: A new oral alternative for cytomegalovirus retinitis in human immunodeficiency virus-seropositive individuals. Pharmacother 22:1124, 2002.

434. Peskovitz MD, Rabkin J, Merion RM et al: Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients. Antimicrob Agents Chemother 44:2811, 2000.

435. Lalezari J, Lindley J, Walmsley S et al: A safety study of oral valganciclovir maintenance treatment of cytomegalovirus retinitis. J Acquir Immune Defic Syndr 30:392, 2002.

435a. Nichols WG, Boeckh M: Recent advances in the therapy and prevention of CMV infections. J Clin Virol 16:25, 2000.

436. Boivin G, Gadreau GC, Greenfield I et al: Rate of emergence of cytomegalovirus (CMV) mutations in leukocytes of patients with acquired immunodeficiency syndrome who are receiving valganciclovir as induction and maintenance therapy for CMV retinitis. J Infect Dis 184:1598, 2001.

437. Palestine AG, Polis MA, DeSmet MD et al: A randomized controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med 115:665, 1991.

438. Balfour HH, Benson C, Braun J et al: Management of acyclovir-resistant herpes simplex and varicella-zoster infections. J Acquir Immune Defic Syndr 7:254, 1994.

439. Wagstaff AJ, Bryson HM: Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections. Drugs 48:199, 1994.

440. Jacobson MA, Crowe S, Levy J et al: Effect of foscarnet therapy on infection with human immunodeficiency virus in patients with AIDS. J Infect Dis 158:862, 1988.

441. Oberg B: Antiviral effects of phosphonoformate (PFA foscarnet sodium). Pharmacol Ther 19:387, 1983.

442. Sandstrom EG, Kaplan JC, Byington RE et al: Inhibitor of human T-cell lymphotropic virus type III in vitro by phosphonoformate. Lancet 1:1480, 1985.

443. Kedes DH, Ganem D: Sensitivity of Kaposi's sarcoma–associated herpes virus replication to antiviral drugs: Implications for potential therapy. J Clin Invest 99:2082, 1997.

444. Crumpacker CS: Mechanism of action of foscarnet against viral polymerases. Am J Med 92:3S, 1992.

445. Jacobson MA, Drew WL, Feinberg J et al: Foscarnet therapy for ganciclovir-resistant cytomegalovirus retinitis in patients with AIDS. J Infect Dis 163:1348, 1991.

446. Erice A, Chou S, Biron KK et al: Progressive disease due to ganciclovir-resistant cytomegalovirus in immunocompromised patients. N Engl J Med 320:289, 1989.

447. LeHoang P, Girard B, Robinet M et al: Foscarnet in the treatment of cytomegalovirus retinitis in acquired immune deficiency syndrome. Ophthalmology 96:865, 1989.

448. Jacobson MA, O'Donnell JJ, Mills J: Foscarnet treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. Antimicrob Agents Chemother 33:736, 1989.

449. Sjovall J, Karksson A, Ogenstad S et al: Pharmacokinetics and absorption of foscarnet after intravenous and oral administration to patients with human immunodeficiency virus. Clin Pharmacol Ther 44:65, 1988.

450. Sjovall J, Bergdahl S, Movin G et al: Pharmacokinetics of foscarnet and distribution to cerebrospinal fluid after intravenous infusion in patients with human immunodeficiency virus infection. Antimicrob Agents Chemother 33:1023, 1989.

451. López-Cortés LF, Ruiz-Valderas R, Lucero-Muñoz MJ et al: Intravitreal, retinal, and central nervous system foscarnet concentrations after rapid intravenous administration to rabbits. Antimicrob Agents Chemother 44:756, 2000.

452. Aweeka F, Gambertoglio J, Mills J et al: Pharmacokinetics of intermittently administered intravenous foscarnet in the treatment of acquired immunodeficiency syndrome patients with serious cytomegalovirus retinitis. Antimicrob Agents Chemother 33:742, 1989.

453. Ringden O, Lonnqvist B, Paulin T et al: Pharmacokinetics, safety and preliminary clinical experiences using foscarnet in the treatment of cytomegalovirus infection in allograft recipients. Scand J Infect Dis 17:373, 1986.

454. Noormohamed FH, Youle MS, Higgs CJ et al: Pharmacokinetics and absolute bioavailability of oral foscarnet in human immunodeficiency virus-seropositive patients. Antimicrob Agents Chemother 42:293, 1998.

455. Deray G, Katlama C, Dohen E: Prevention of foscarnet nephrotoxicity. Ann Intern Med 113:332, 1990.

456. Fanning MM, Read SE, Bendon M et al: Foscarnet therapy of cytomegalovirus retinitis in AIDS. J AIDS 3:472, 1990.

457. MacGregor RR, Graziani AL, Weiss R et al: Successful foscarnet therapy for cytomegalovirus retinitis in an AIDS patient undergoing hemodialysis: Rationale for empiric dosing and plasma level monitoring. J Infect Dis 164:785, 1991.

458. Seidel EA, Koenig S, Polis MA: A dose escalation study to determine the toxicity and maximally tolerated dose of foscarnet. AIDS 7:941, 1993.

459. Jacobson MA, Causey D, Polsky B et al: A dose-ranging study of daily maintenance intravenous foscarnet therapy for cytomegalovirus retinitis in AIDS. J Infect Dis 168:444, 1993.

460. Jayaweera DT: Minimising the dosage-limiting toxicities of foscarnet induction therapy. Drug Saf 16:258, 1997.

461. Jacobson MA, Gambertoglio JG, Aweeka FT et al: Foscarnet-induced hypocalcemia and effect of foscarnet on calcium metabolism. J Clin Endocrinol Metab 72:1130, 1991.

462. Youle MS, Clarbour J, Gazzard B et al: Severe hypocalcemia in AIDS patients treated with foscarnet and pentamidine. Lancet 1:1455, 1988.

463. Yusufi ANR, Sczczepanska-Konkel M, Kempson SA et al: Inhibition of human renal epithelial sodium phosphate co-transport by phosphonoformic acid. Biochem Biophys Res Comm 139:670, 1986.

464. Jacobson MA, Wulfsohn M, Feinberg JE et al: Phase II dose-ranging trial of foscarnet salvage therapy for cytomegalovirus retinitis in AIDS patients intolerant of or resistant to ganciclovir (ACTG Protocol 093). AIDS 8:451, 1994.

465. Farthing CI, Dalgleish AG, Clark A et al: Phosphonoformate (foscarnet): A pilot study in AIDS and AIDS related complex. AIDS 1:21, 1987.

466. Walmsley SL, Chew E, Read SE et al: Treatment of cytomegalovirus retinitis with trisodium phosphonoformate hexahydrate (Foscarnet). J Infect Dis 157:569, 1988.

467. Farese RV Jr, Schambelan M, Hollander H et al: Nephrogenic diabetes insipidus associated with foscarnet treatment of cytomegalovirus retinitis. Ann Intern Med 112:955, 1990.

468. Gilquin J, Weiss L, Kazatchkinl MD: Genital and oral erosions induced by foscarnet. Lancet 335:287, 1990.

469. Van der Pijl JW, Frisser PHJ, Reiss P et al: Foscarnet and penile ulceration. Lancet 335:286, 1990.

470. Safrin S, Kemmerly S, Plotkin B et al: Foscarnet-resistant herpes simplex virus infection in patients with AIDS. J Infect Dis 169:193, 1994.

470a. Jabs DA, Enger C, Forman M, Dunn JP: Incidence of foscarnet resistance and cidofovir resistance in patients treated for cytomegalovirus retinitis. The Cytomegalovirus Retinitis and Viral Resistance Study Group. Antimicrob Agents Chemother 42:2240, 1998.

471. Safrin S, Grumpacker C, Chatis P et al: A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. N Engl J Med 325:551, 1991,

472. Apperly JF, Marcus RE, Goldman JM et al: Foscarnet for cytomegalovirus pneumonitis [Letter]. Lancet 1:1151, 1985.

473. Klintmalm G, Lonnqvist B, Oberg B et al: Intravenous foscarnet for the treatment of severe cytomegalovirus infection in allograft recipients. Scand J Infect Dis 17:157, 1985.

474. Nelson MR, Connolly GM, Hawkins DA et al: Foscarnet in the treatment of cytomegalovirus infection of the esophagus and colon in patients with the acquired immune deficiency syndrome. Am J Gastroenterol 86:876, 1991.

475. Dieterich DT, Poles MA, Dicker M et al: Foscarnet treatment of cytomegalovirus gastrointestinal infections in acquired immunodeficiency syndrome patients who have failed ganciclovir induction. Am J Gastroenterol 88:542, 1993.

476. Jacobson MA, Van der Horst C, Causey DM et al: In vivo additive antiretroviral effect of combined zidovudine and foscarnet therapy for human immunodeficiency virus infection (ACTG Protocol 053). J Infect Dis 163:1219, 1991.

477. Bergdahl S, Jacobsson B, Moberg L et al: Pronounced anti-HIV-1 activity of foscarnet in patients without cytomegalovirus infection. J Acquir Immune Defic Syndr Hum Retrovirol 18:51, 1998.

478. Glesby MJ, Hoover DR, Weng S et al: Use of antiherpes drugs and the risk of Kaposi's sarcoma: Data from the Multicenter AIDS Cohort Study. J Infect Dis 173:1477, 1996.

479. Holland GN, Levinson RD, Jacobson MA,The AIDS Clinical Trials Group Protocol 915 Team: Dose-related difference in progression rates of cytomegalovirus retinopathy during foscarnet maintenance. Am J Ophthalmol 119:576, 1995.

480. Freitas VR, Fraser-Smith EB, Matthews TR: Increased efficacy of ganciclovir in combination with foscarnet against cytomegalovirus and herpes simplex virus type 2 in vitro and in vivo. Antiviral Res 12:205, 1989.

481. Manischewitz JF, Quinnan GV Jr, Lane HC et al: Synergistic effect of ganciclovir and foscarnet on cytomegalovirus replication in vitro. Antimicrob Agents Chemother 34:373, 1990.

482. Diaz-Lopez M, Chipont E, Sanchez S et al: Intravitreal foscarnet for cytomegalovirus retinitis in a patient with acquired immunodeficiency syndrome. Am J Ophthalmol 114:742, 1992.

483. Diaz-Lopez, España E, Muñoz G et al: High dose intravitreal foscarnet in the treatment of cytomegalovirus retinitis in AIDS. Br J Ophthalmol 78:120, 1994.

484. Pearson PA, Jaffe GJ, Ashton P: Intravitreal foscarnet for cytomegalovirus retinitis in a patient with acquired immunodeficiency syndrome [Letter]. Am J Ophthalmol 115:686, 1993.

485. Hitchcock MJM, Jaffe HS, Martin JC et al: Cidofovir, a new agent with potent anti-herpes virus activity. Antiviral Chem Chemother 7:115, 1996.

486. Bronson JJ, Ghazzouli I, Hitchcock MJM et al: Synthesis and antiviral activity of the nucleotide analogue (s)-1-[3-hydroxy-2-(phosphonylmethoxy) propyl]cytosine. J Med Chem 32:1457, 1989.

487. Safrin S, Cherrington JM, Jaffe HS: Clinical uses of cidofovir. Rev Med Virol 7:145, 1997.

488. Ho HT, Woods KL, Bronson JJ et al: Intracellular metabolism of the anti herpes agent (s)-1-[3-hydroxy-2-(phosphonylmethoxy) propyl] cytosine. J Med Chem 32:1457, 1989.

489. Plosker GL, Noble S: Cidofovir. A review of its use in cytomegalovirus retinitis in patients with AIDS. Drugs 58:325, 1999.

490. Mulato MS, Cherrington JM, Chen MS: Anti-HCMV activity of cidofovir in combination with antiviral compounds and immunosuppressive agents: in vitro analyses. Antiviral Chem Chemother 7:203, 1996.

491. Kundy KC: Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir. Clin Pharmacokinet 36:127, 1999.

492. Polis MA, Spooner KM, Baird BF et al: Anticytomegaloviral activity and safety of cidofovir in patients with human immunodeficiency virus infection and cytomegalovirus viruria. Antimicrob Agents Chemother 39:882, 1995.

493. Lalezari JP, Stagg RJ, Kuppermann BD et al. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. Ann Intern Med 126:257,1997.

494. Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group: Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: The HPMPC Peripheral Cytomegalovirus Retinitis Trial. Ann Intern Med 126:264, 1997.

495. LaLezari JP, Holland GN, Kramer F et al: Randomized, controlled study of the safety and efficacy of intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 17:339, 1998.

496. The Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trial Group: Long-term follow-up of patients with AIDS treated with parenteral cidofovir for cytomegalovirus retinitis: The HPMPC Peripheral Cytomegalovirus Retinitis Trial. AIDS 14:1671, 2000.

497. Davis JL, Taskintuna I, Freeman WR et al: Iritis and hypotony after treatment with intravenous cidofovir for cytomegalovirus retinitis. Arch Ophthalmol 115:733, 1997.

498. Akler ME, Johnson DW, Burman WJ et al: Anterior uveitis and hypotony after intravenous cidofovir for the treatment of cytomegalovirus retinitis. Ophthalmology 105:651, 1998.

499. Ambati J, Wynne KB, Angerame MC et al: Anterior uveitis associated with intravenous cidofovir use in patients with cytomegalovirus retinitis. Br J Ophthalmol 83:1153, 1999.

500. Kirsch LS, Arevalo JF, Chavez de la Paz E et al: Intravitreal cidofovir treatment of cytomegalovirus retinitis in patients with acquired immune deficiency syndrome. Ophthalmology 103:533, 1995.

501. Friedberg DN: Hypotony and visual loss with intravenous cidofovir treatment of cytomegalovirus retinitis. Arch Ophthalmol 115:801, 1997.

502. Banker AS, Arevalo JF, Munguia D et al: Intraocular pressure and aqueous humor dynamics in patients with AIDS treated with intravitreal cidofovir (HPMPC) for cytomegalovirus retinitis. Am J Ophthalmol 124:168, 1997.

503. Taskintuna I, Rahhal FM, Rao NA et al: Adverse events and autopsy findings after intravitreous cidofovir (HPMPC) therapy in patients with acquired immune deficiency syndrome (AIDS). Ophthalmology 104:1827, 1997.

504. Lea AP, Bryson HM: Cidofovir. Drugs 52:225, 1996.

505. Anonymous: Drugs for non-HIV viral infections. Medical Letter 44:9, 2002.

506. Anonymous: Smallpox vaccine. Medical Letter 45:1, 2003.

507. Jacobson MA, Wilson S, Stanley H et al: Phase I Study of combination therapy with intravenous cidofovir and oral ganciclovir for cytomegalovirus retinitis in patients with AIDS. J Infect Dis 28:528, 1999.

508. The Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group: MSL-109 adjuvant therapy for cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome. The Monoclonal Antibody Cytomegalovirus Retinitis Trial. Arch Ophthalmol 115:1527, 1997.

509. Rahhal FM, Arevalo JF, Munguia D et al: Intravitreal cidofovir for the maintenance treatment of cytomegalovirus retinitis. Ophthalmology 103:1078, 1996.

510. Taskintuna I, Rahhal FM, Arevalo JF et al: Low-dose intravitreal cidofovir (HPMPC) therapy of cytomegalovirus retinitis in patients with acquired immune deficiency syndrome. Ophthalmology 104:1049, 1997.

511. Kupperman BD, Wolitz R, Stagg R et al: A Phase II randomized, double-masked study of intraocular cidofovir for relapsing cytomegalovirus retinitis (CMV-R) in patients with AIDS [abstract]. Vitreous Society Annual Meeting, Cancun, Mexico, Dec. 9–12, 1996.

512. Gordon YJ, Romanowski E, Aravullo-Cruz T et al: Inhibitory effect of (s)-HPMPC, (s)-HPMPA, and 2' nor-cyclic GMP on clinical ocular adenoviral isolates is serotype-dependent in vitro. Antiviral Res 16:11, 1991.

513. Hillenkamp J, Reinhard T, Ross RS et al: The effects of cidofovir 1% with and without cyclosporin A 1% as a topical treatment of acute adenoviral keratoconjunctivitis. A controlled clinical pilot study. Ophthalmology 109:845, 2002.

514. Hillenkamp J, Reinhard T, Ross RS et al: Topical treatment of acute adenoviral keratoconjunctivitis with 0.2% cidofovir and 1% cyclosporine. A controlled clinical pilot study. Arch Ophthalmol 119:1487, 2001.

515. Geary RS, Henry SP, Grillone LR: Fomivirsen. Clinical pharmacology and potential drug interactions. Clin Pharmacol 41:255, 2002.

516. Perry CM, Balfour JAB: Fomivirsen. Drugs 57:375, 1999.

517. Freeman WR: Retinal toxic effects associated with intravitreal fomivirsen. Arch Ophthalmol 119:458, 2001.

518. Jabs DA, Griffiths PD: Fomivirsen for the treatment of cytomegalovirus retinitis. Am J Ophthalmol 133:552, 2002.

519. Azad RF, Driver VB, Tanaka K: Antiviral activity of a phosphorothioate oligonucleotide complementary to RNA of the human cytomegalovirus major immediate-early region. Antimicrob Agents Chemother 37:1945, 1993.

520. Anderson KP, Fox, MC, Brown-Driver V et al: Inhibition of human cytomegalovirus immediate-early gene expression by an antisense oligonucleotide complementary to immediate-early RNA. Antimicrob Agents Chemother 40:2004, 1996.

521. Azad R, Brown-Driver V, Buckheit RW Jr et al: Antiviral activity of a phosphorothioate oligonucleotide complementary to human cytomegalovirus RNA when used in combination with antiviral nucleoside analogs. Antiviral Res 28:101, 1995.

522. Flores-Aguilar M, Besen G, Vyong C et al: Evaluation of retinal toxicity and efficacy of anti-cytomegalovirus and anti-herpes simplex virus antiviral phosphorothioate oligonucleotides ISIS 2922 and ISIS 4015. J Infect Dis 6:1308, 1997.

523. Benjamin M, Lieberman RM, Goldstein DA et al: A pharmacokinetic study of intravitreal fomivirsen (Vitravene™) in patients with CMVR. ARVO Annual Meeting, May 9–14, 1999. Fort Lauderdale: 10VS 40:5874, 1999.

524. Leeds JM, Henry SP, Truong L et al: Pharmacokinetics of a potential human cytomegalovirus therapeutic, a phosphorothoriate oligonucleotide after intravitreal injection in the rabbit. Drug Metab Dispos 25:921, 1997.

525. The Vitravene Study Group: The safety of intravitreous fomivirsen for treatment of cytomegalovirus retinitis in patients with AIDS. Am J Ophthalmol 133:484, 2002.

526. Amin HI, Ai E, McDonald HR: Retinal toxic effects associated with intravitreal fomivirsen. Arch Ophthalmol 118:426, 2000.

527. Uwaydat SH, Li HK: Pigmentary retinopathy associated with intravitreal fomivirsen. Arch Ophthalmol 120:854, 2002.

528. Zambarakji HJ, Mitchell SM, Lightman S et al: Electrophysiological abnormalities following intravitreal vitravene (ISIS 2922) in two patients with CMV retinitis. Br J Ophthalmol 85:1142, 2001.

529. Stone TW, Jaffe GJ: Reversible bull's-eye maculopathy associated with intravitreal fomivirsen therapy for cytomegalovirus retinitis. Am J Ophthalmol 130:242, 2000.

530. The Vitravene Study Group: A randomized controlled trial of intravenous fomivirsen for treatment of newly diagnosed peripheral cytomegalovirus retinitis in patients with AIDS. Am J Ophthalmol 133:467, 2002.

531. The Vitravene Study Group: Randomized dose-comparison studies of intravitreous fomivirsen for treatment of cytomegalovirus retinitis that has reactivated or is persistently active despite other therapies in patients with AIDS. Am J Ophthalmol 133:475, 2002.

532. Palella FJ Jr, Delaney KM, Moorman AC et al: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 338:853, 1998.

533. Jabs DA, Bartlett JG: AIDS and ophthalmology: A period of transition. Am J Ophthalmol 124:227, 1997.

534. Jacobson MA, Stanley H, Holtzer C et al: Natural history and outcome of new AIDS-related cytomegalovirus retinitis diagnosed in the era of highly active antiretroviral therapy. Clin Infect Dis 30:231, 2000.

535. Jabs DA, Van Natta ML, Kempen JH et al: Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol 133:48, 2002.

536. Whitcup SM, Fortin E, Nussenblatt RB et al: Therapeutic effect of combination antiretroviral therapy on cytomegalovirus retinitis. JAMA 277:1519, 1997.

537. Whitcup SM, Fortin E, Lindblad S et al: Discontinuation of anticytomegalovirus therapy in patients with HIV infection and cytomegalovirus retinitis. JAMA 282:1633, 1999.

538. Macdonald JC, Torriani FJ, Morse LS et al: Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T-cells in response to highly active antiretroviral therapy. J Infect Dis 177:1182, 1998.

539. Jabs, DA, Bolton SG, Dunn JP et al: Discontinuing anticytomegalovirus therapy in patients with immune reconstitution after combination antiretroviral therapy. Am J Opthalmol 126:817, 1998.

540. Jovan MA, Saves JM, Tubiana R et al: Discontinuation of maintenance therapy for cytomegalovirus retinitis in HIV-infected patients receiving highly active antiretroviral therapy. AIDS 15:23, 2001.

541. Whitcup SM, Cunningham ET Jr, Polis MA et al: Spontaneous and sustained resolution of CMV retinitis in patients receiving highly active antiretroviral therapy. Br J Ophthalmol 82:845, 1998.

542. Reed JB, Schwab IR, Gordon J et al: Regression of cytomegalovirus retinitis associated with protease-inhibitor treatment in patients with AIDS. Am J Ophthalmol 124:199, 1997.

543. Vrabec TR, Baldassano VF, Whitcup SM: Discontinuation of maintenance therapy in patients with quiescent cytomegalovirus retinitis and elevated CD4+ counts. Ophthalmology 105:1259, 1998.

544. Michelet C, Arvieux C, Francois C et al: Opportunistic infections occurring during highly active antiretroviral treatment. AIDS 12:1815, 1998.

545. Jacobson MA, Zegans M, Pavan PR et al: Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 349:1443, 1997.

546. Song MK, Karavellas MP, Macdonald JC et al: Characterization of reactivation of cytomegalovirus retinitis in patients healed after treatment with highly active antiretroviral therapy. Retina 20:151, 2000.

547. Lin DY, Warren JF, Lazzeroni LC et al: Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy in HIV-infected patients Natural history and clinical predictors. Retina 22:268, 2002.

548. Torriani FJ, Freeman WR, Macdonald JC et al: CMV retinitis recurs after stopping treatment in virological and immunological failure of potent antiretroviral therapy. AIDS 14:173, 2000.

549. Song MK, Schrier RD, Smith IL et al: Paradoxical activity of CMV retinitis in patients receiving highly active antiretroviral therapy. Retina 22:262, 2002.

550. Jacobson MA, Schrier R, McCune JM et al: Cytomegalovirus (CMV)-specific CD4+ T lymphocyte immune function in long-term survivors of AIDS-related CMV end-organ disease who are receiving potent antiretroviral therapy. J Infect Dis 1399, 2001.

551. Kuppermann BD, Holland GN: Immune Recovery Uveitis. Am J Ophthalmol 130:103, 2000.

552. Karavellas MP, Plummer DJ, Macdonald JC et al: Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. J Infect Dis 179:697, 1999.

553. Robinson MR, Reed G, Csaky KG et al: Immune-recovery uveitis in patients with cytomegalovirus retinitis taking highly active antiretroviral therapy. Am J Ophthalmol 130:49, 2000.

554. Nguyen QD, Kempen JH, Bolton SG et al: Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy. Am J Ophthalmol 129:634, 2000.

555. Karavellas MP, Azen SP, Macdonald JC et al: Immune recovery vitritis and uveitis in AIDS. Clinical predictors, sequelae, and treatment outcomes. Retina 21:1, 2001.

556. Henderson HW, Mitchell SM: Treatment of immune recovery vitritis with local steroids. Br J Ophthalmol 83:540, 1999.

557. Panda A, Das GK, Khokhar S et al: Efficacy of four antiviral agents in the treatment of uncomplicated herpetic keratitis. Can J Ophthalmol 30:256, 1995.

558. Wutzler P: Antiviral therapy of herpes simplex and varicella-zoster virus infections. Intervirology 40:343, 1997.

559. Gnann JW Jr, Crumpacker CS, Lalezari JP et al: Sorivudine versus acyclovir for treatment of dermatomal herpes zoster in human immunodeficiency virus–infected patients: Results from a randomized, controlled clinical trial. Collaborative Antiviral Study Group/AIDS Clinical Trials Group, Herpes Zoster Study Group. Antimicrob Agents Chemother 42:1139, 1998.

560. Genovesi EV, Lamb L, Medine I et al: Antiviral efficacy of lobucavir (BMS-180194), a cyclobutyl-guanosine nucleoside analogue, in the woodchuck (Marmota monax) model of chronic hepatitis B virus (HBV) infection. Antiviral Res 48:197, 2000.

561. Tenney DJ, Yamanaka G, Voss SM et al: Lobucavir is phosphorylated in human cytomegalovirus-infected and -uninfected cells and inhibits the viral DNA polymerase. Antimicrob Agents Chemother 41:2680, 1997.

562. Lalezari J, Drew WL, Jordan C: In vivo anti-CMV activity and safety of oral lobucavir in HIV-infected patients (protocol AI 459-007 [Abstract 301]. 9th Conference on Retroviruses and Opportunistic Infections, 1997.

563. Wilber R, Buffington D, Tyring S: Efficacy and safety of oral lobucavir (LBV) in patients with recurrent genital herpes. The 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, Abs H-86, 339, 1998.

564. Reefschlaeger J, Bender W, Hallenberger S et al: Novel non-nucleoside inhibitors of cytomegaloviruses (BAY38-4766): In vitro and in vivo antiviral activity and mechanism of action. J Antimicrob Chemother 757, 2001.

565. McSharry JJ, McDonough A, Olson B et al: Susceptibilities of human cytomegalovirus clinical isolates to BAY38-4766, BAY 43-9695, and ganciclovir. Antimicrob Agents Chemother 45:2925, 2001.

566. Evers DL, Komazin G, Shin D et al: Interactions among antiviral drugs acting late in the replication cycle of human cytomegalovirus. Antiviral Res 56:61, 2002.

567. Lalezari JP, Aberg JA, Wang LH et al: Phase I dose escalation trial evaluating the pharmacokinetics, anti-human cytomegalovirus (HCMV) activity, and safety of 1263W94 in human immunodeficiency virus–infected men with asymptomatic HCMV shedding. Antimicrob Agents Chemother 46:2969, 2002.