Chapter 37
Topical and Systemic Antiviral Agents
STEVEN A. TEICH and TONY W. CHEUNG
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IDOXURIDINE
TRIFLURIDINE
VIDARABINE
ACYCLOVIR
VALACYCLOVIR
FAMCICLOVIR/PENCICLOVIR
GANCICLOVIR
VALGANCICLOVIR
FOSCARNET
CIDOFOVIR
FOMIVIRSEN
HAART FOR HIV DISEASE
INVESTIGATIONAL AGENTS
REFERENCES

Antiviral chemotherapy has lagged behind the development of antibiotics for bacterial infections. Because bacteria are relatively complex self-replicating organisms, they have many metabolic differences from mammalian cells that can be selectively attacked by drugs. Viruses, however, are much more primitive. As obligatory intracellular parasites, viruses replicate only by invading a cell and utilizing the host's biochemical mechanisms to synthesize new viral proteins and genetic material. Until recently, it was difficult to find drugs that would inhibit viral functions without also damaging the host cell. Over the past 2 decades, however, the recognition of viral enzymes and proteins that can serve as molecular targets for drugs has revolutionized the treatment of viral infections. All currently available antiviral agents are virustatic and require an intact immune system to maintain the suppression of many viral infections.

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


Drug Preparation Dosagea
Trifluridine 1% solution Initially, 1 drop every 2 hours while awake (maximum, 9 drops daily). When healing appears to be complete, treatment should be continued for 7 days at a dosage of 1 drop every 4 hours while awake (minimum, 5 drops daily).
Vidarabine 3% ointment One-half inch applied daily at 3-hour intervals. When healing appears to be complete, treatment should be continued for 7 days at a reduced dosage (e.g., twice daily).
Idoxuridineb 0.1% solution One drop every 2 hours during the day and every 4 hours at night. Treatment should be continued for 3 to 5 days after healing appears to be complete.
  0.5% ointment One-half inch applied every 4 hours while awake. Treatment should be continued for 3 to 5 days after healing appears to be complete
Acyclovirc (investigational) 3% ointment One-half inch applied five times daily at 3- to 4-hour intervals and continued for at least 3 days after complete healing.

aNone of these agents should generally be used for more than 14 to 21 days.
bNo longer generally available.
cThe dermal ointment 5% should not be used in place of the investigational ophthalmic ointment.

 

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.

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IDOXURIDINE
Idoxuridine (5-iodo-2'-deoxyuridine; IDU) became the first clinically effective antiviral agent when it was shown to be useful for the topical treatment of HSV epithelial keratitis.1–7 It has been supplanted by the related, but more effective, thymidine analog trifluridine (Fig. 1).

Fig. 1. Chemical structure of the thymidine analogs idoxuridine (A) and trifluridine (C) and of thymidine (B).

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.

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TRIFLURIDINE
Trifluridine (5-trifluoromethyl-2'-deoxyuridine, trifluorothymidine), like IDU, is a thymidine analog, but it is a far more potent antiviral agent than IDU. Originally synthesized as an anticancer agent,27 it was too toxic for systemic use28 but was found to be effective topically for the treatment of HSV keratitis.29 Trifluridine is the drug of choice for the topical treatment of herpetic epithelial keratitis.

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-26a,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.

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VIDARABINE
Vidarabine (9-β-D-arabinosyladenine; adenine arabinoside; ara-A) was the second agent licensed for topical treatment of HSV epithelial keratitis. It was the first antiviral agent to be licensed for systemic use against life-threatening viral infections (i.e., HSV encephalitis), but it has been replaced for this use by acyclovir, which is more effective, less toxic, and more easily administered.

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.

Fig. 2. Chemical structures of systemic antiviral agents. A, adenine analog; G. guanosine analog.

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 interferon71a 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 adults75–76a 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 keratitis39,47,48 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.

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ACYCLOVIR
Acyclovir (9-[2-hydroxyethoxymethyl] guanine) has proved to be an extremely safe and effective agent and is a drug of choice for most forms of HSZ and VZV infections. Its availability in topical, oral, and intravenous preparations allows its use in a wide range of clinical situations. However, its poor oral absorption has spurred the development of valacyclovir and famciclovir.

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, tear105,106 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% cream140a 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 IDU111,173,174 and equivalent to vidarabine175–178 or trifluridine179,180 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 acyclovir105,106,181 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 situation185–187; 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-workers156,157 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 investigators210,211 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 therapy77,148–150,152 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 ARN108,237 but are difficult to maintain with oral therapy.103

Acyclovir given intravenously allows more rapid resolution of the retinitis234,237–239 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

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VALACYCLOVIR
Valacyclovir, the L-valyl ester of acyclovir, is a prodrug that is rapidly and nearly completely converted to acyclovir after oral administration. Its excellent bioavailability results in serum acyclovir levels comparable to intravenous acyclovir but requiring less frequent dosing than oral acyclovir. Therefore, it has much the same antiviral indications and safety as oral acyclovir with the advantage of simpler dosing.

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.

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FAMCICLOVIR/PENCICLOVIR
Famciclovir is the diacetyl-6-deoxyester pro-drug of the acyclic guanosine analog penciclovir (9-[4-hydroxy-3-hydroxymethylbut-1-yl] guanine), which is its active moiety. In a manner analogous to valacyclovir, oral famciclovir is well absorbed and rapidly metabolized in the intestine and liver to penciclovir. Penciclovir (itself poorly absorbed orally) is similar to acyclovir in its activity and potency against herpesviruses.301

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.

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GANCICLOVIR
Ganciclovir (DHPG; 9-[1,3-dihydroxy-2-propoxymethyl] guanine) was the first drug to be approved by the Food and Drug Administration (FDA) for use in the treatment of CMV retinitis in immunocompromised patients. Although immunosuppressed patients also appear to derive some benefit from ganciclovir for CMV infections of the lung and gastrointestinal tract, the evidence of ganciclovir efficacy for these infections is less clear-cut.

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 isolates317,322 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 colleagues354a 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 therapy392a,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 foscarnet424,425 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 hemorrhage414–416,418,422 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

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VALGANCICLOVIR
Valganciclovir is a valyl ester prodrug of ganciclovir that is well absorbed orally and rapidly metabolized to ganciclovir. It provides ganciclovir blood levels comparable to intravenous ganciclovir and was approved by the FDA in 2001 for both induction and maintenance treatment of CMV retinitis in patients with AIDS. It will undoubtedly replace oral and probably intravenous ganciclovir as the drug of choice for most cases of CMV retinitis as well as other CMV infections.

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 (AUC24h) 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.

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FOSCARNET
Foscarnet (phosphonoformic acid; PFA) has been approved by the FDA to treat CMV retinitis in patients with AIDS, for which it is about as effective as ganciclovir and, prior to effective antiretroviral therapy, may have had a survival benefit.411,437 It differs from previously discussed antiviral agents in that it is a pyrophosphate analog rather than a nucleoside analog. Foscarnet is useful in the treatment of CMV infections in immunocompromised patients who are unresponsive to, or intolerant of, ganciclovir and in the treatment of acyclovir-resistant herpetic infections.62,438 Foscarnet offers an advantage over ganciclovir in that it does not lower the neutrophil or platelet count and, therefore, can be used concomitantly with the antiretroviral agent zidovudine. Unfortunately, foscarnet must be administered intravenously.

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 infections265,269,270,274,438 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.

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CIDOFOVIR
Cidofovir is the first antiviral nucleotide analogue to be used clinically. It has been approved only for intravenous therapy of CMV retinitis in AIDS patients. The prolonged intracellular half-life of its active diphosphate allows infrequent dosing and obviates the need for an indwelling catheter. Unfortunately, it frequently causes nephrotoxicity and uveitis.

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 approval489,493–495 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 doses497,498 (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 inhibitors406,496,497 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 patients493,494 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

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FOMIVIRSEN
Fomivirsen is the first of a new class of drugs called antisense oligonucleotides to be used clinically. It is a potent and selective antiviral to human CMV, designed to bind complementary regions of CMV messenger RNA. Thus it differs from the previous agents discussed in not being an inhibitor of viral DNA polymerase.515,516 It is administered only via intravitreal injections and thus shares with the ganciclovir implant the advantages and disadvantages of local therapy. The incidence and severity of ocular toxicity has not been completely elucidated, and there is some evidence indicating a narrow therapeutic ratio.517,518 It is approved in the U.S. for the local treatment of CMV retinitis in patients with AIDS who are intolerant of or have a contraindication to other treatments for CMV retinitis or who have been insufficiently responsive to previous treatments.

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

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HAART FOR HIV DISEASE
The introduction of protease inhibitors in late 1996 in combination with at least two nucleoside inhibitors, referred to as highly active antiretroviral therapy or HAART (see Table 2), had a profound effect on AIDS-related morbidity and mortality.532 HAART, in general, has led to reductions in HIV viral loads, elevations of CD4+ T-cell counts, and a reduction in morbidity and mortality related to AIDS. It has also led to a marked reduction (55% to 80%) in the incidence of CMV retinitis (CMVR),532–534 and the natural history of CMVR has been altered in patients with immune recovery.534,535 Clinical reports over the past few years suggest that many patients with immune recovery who are receiving HAART and have inactive CMVR can safely discontinue anti-CMV therapy.534–540 Other reports suggest that HAART can allow CMVR to resolve in some patients without specific anti-CMV treatment.541–543 However, new cases of CMVR and other opportunistic infections have been reported within 2 or 3 months of the initiation of HAART, and HAART may need to be given for several months before the immune system is able to control or prevent opportunistic infections.544,545 CMVR may recur or occur for the first time in patients failing HAART therapy, especially when CD4 counts decrease below 100.535,546–548

 

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
  Atazanavira
  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)a

aExperimental 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


Patient CharacteristicsUnilateral DiseaseBilateral or Systemic Disease
HAART-Naïve  
Initial therapyIV ganciclovir or foscarnet or oral valganciclovir plus HAARTIV ganciclovir or foscarnet or oral valganciclovir plus HAART
Maintenance therapyIf HAART responder, oral ganciclovir or valganciclovir; consider close observation trial off therapyaIf HAART responder; oral ganciclovir or valganciclovir; consider close observation trial off therapya
 If HAART nonresponder; IV ganciclovir or foscarnet; consider ganciclovir implant plus oral valganciclovirIf HAART nonresponder; IV ganciclovir or foscarnet; consider ganciclovir implant plus oral valganciclovir
Salvage therapyCombination IV ganciclovir and foscarnet or ganciclovir implant or intraocular fomivirsen; plus HAARTCombination IV ganciclovir and foscarnet or ganciclovir implant or intraocular formisen; plus HAART or bilateral ganciclovir implant with oral ganciclovir or valganciclovir
HAART-Experienced  
Initial therapyIV ganciclovir followed shortly by ganciclovir implant plus oral valganciclovir therapyIV ganciclovir or foscarnet or cidofovir
Salvage therapyCombination IV ganciclovir and foscarnet or cidofovir or intraocular fomivirsenCombination IV ganciclovir and foscarnet or IV cidofovir or bilateral ganciclovir implant with oral ganciclovir or valganciclovir

AIDS, acquired immunodeficiency syndrome; CMV, cytomegalovirus; HAART, highly active antiretroviral therapy; IV, intravenous.
aIf CD4 lymphocyte count increases to greater than 100–150 cells for 3 to 6 months or longer, with corresponding reduction in human immunodeficiency virus viral load.

 

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

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INVESTIGATIONAL AGENTS
Brivudin, a thymidine nucleoside analog, is an effective topical agent against HSV-1 epithelial keratitis but is only available in Europe.557 The most potent antiviral agent ever developed for the treatment of HZV infections is sorivudine (BV-ara U) whose 50% inhibitory concentration is 1000 times more active than that of acyclovir. This drug was withdrawn from the Japanese market in 1993 after 18 deaths in patients concurrently receiving 5-fluorouracil.216,558 Bromovinyluracil, a metabolite of sorivudine, inhibits the hepatic enzyme dihydropyrimidine dehydrogenase, which normally metabolizes 5-FU. Without this enzyme, 5-FU serum concentrations rapidly rise to fatal levels. Although a recent controlled trial demonstrated that once-daily 40-mg dosage of sorivudine was superior to acyclovir in treating HZV in immunocompromised patients, the FDA has indicated that it will not approve this drug and the sponsoring company has discontinued its development.559

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.

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