Attachment and penetration require interaction between virus-specific structures with cellular plasma membranes. Uncoating is usually done by cellular enzymes but may be affected by virus-specific proteins. Viral DNA moves to the nucleus where it is transcribed into messenger RNA (mRNA) by cellular RNA polymerase, a process that also may be affected by viral-specific proteins. The mRNAs then migrate back to the cytoplasm where they sequentially regulate synthesis of virus specific proteins. Key nonstructural proteins (enzymes) include virus-specific thymidine kinase, DNA polymerase, DNase, and ribonucleotide reductase. Synthesis of the DNA viruses of ophthalmic interest occurs in the nucleus, catalyzed by virus-specific DNA polymerase. Capsids and nuclear material are assembled and, in some cases (herpesviruses), host-derived nuclear membranes are acquired before migration of mature organisms to the cell surface for release.

Numerous sites target viral specific functions throughout the replicative cycle. Current antiviral therapy and research focuses on these functions, targeting components as varied as enzymes more specific to virus than cell to virus–specific gene fragments (Table 1).

Table 1. FDA-Approved Antiviral Agents for Ocular Disease

STRUCTURE

Idoxuridine (IDU), the pyrimidine antimetabolite 5-iodo-2'-deoxyuridine, which was introduced commercially in 1962, was the first drug used to control human viral disease.^10,11 Structurally, IDU is a thymidine analog with the 5'-methyl group replaced by iodine (Fig. 1 A and B).

MECHANISMS OF ACTION

IDU is incorporated as a thymidine analog preferentially into viral DNA over cellular DNA, as the former replicates more rapidly in infected cells^8,10,11 (see Table 1). The drug is not selectively activated but is phosphorylated by both viral and cellular kinases. The IDU triphosphate also inhibits the virus-specific DNA polymerase more than it inhibits the host cell polymerases. IDU may interact specifically with dTMP synthetase or it may be incorporated directly into DNA as IDU monoposphate.¹² Substitution of IDU for thymidine in the DNA chain leads to abnormal transcription and translation, thus producing defective viral progeny. Its incorporation into some host DNA adds to the toxicity of the agent.

Although IDU and its phosphorylated metabolites inhibit a variety of cellular enzymes, IDU action as an antiherpetic agent may also occur at a viral biosynthetic level prior to incorporation into the viral genome.¹⁰ Phosphorylation of IDU to the triphosphate form (IDUTP) allows this compound to mimic deoxythymidine triphosphate (dTTP), and subsequently IDUTP may exert either an allosteric or a feedback inhibitory effect at the level of dT kinase, deoxycytidine monophosphate deaminase, or cytidine diphosphate (CDP) reductase, ultimately terminating viral replication.¹²

TOXICITY

The toxic effects of IDU are magnified in tissues undergoing rapid cellular DNA synthesis.¹³ Clinical trials using the drug systemically for HSV encephalitis revealed that the drug was minimally effective and highly toxic.¹⁴ IDU is teratogenic, mutagenic, and potentially carcinogenic. For these reasons it is not used as a systemic agent.

In the eye, adverse reactions to topical IDU include contact dermatitis, punctate epithelial keratopathy, follicular conjunctivitis, lacrimal punctal stenosis and occlusion, and lid margin keratinization.¹⁵ IDU is the most toxic of the commonly used topical antiviral drugs, interfering primarily with stromal healing and causing toxic epithelial changes.¹⁶

PENETRATION AND PHARMACOKINETICS

In rabbits treated with 0.5% IDU ointment, the drug did not penetrate the intact cornea.¹⁷ In human ocular penetration studies, IDU, as the parent nucleoside, did not enter the aqueous humor. Instead, uracil, a metabolic breakdown product of IDU, was detected in the aqueous. Only in patients in whom the corneal epithelium was damaged did IDU penetrate the cornea. When administered systemically (intravenously, intramuscularly, or subcutaneously), the drug is dehalogenated and rapidly metabolized; 50% to 75% is excreted within 4 to 5 hours following systemic administration in animals.^18,19

EFFICACY

IDU is used topically and only for HSV keratitis. In vitro studies demonstrated that IDU did not affect the adsorption of HSV in tissue culture cell monolayers, nor did it alter the infectivity of extracellular herpesvirus. IDU did stop viral replication after it had begun and resulted in at least a 2-log unit diminution in viral titers 24 hours post treatment.^20,21 The antiviral efficacy of IDU was substantiated in numerous controlled clinical trials.^22,23 Healing rates vary from about 75% in complicated cases to 90% in straightforward dendritic or geographic keratitis. When 0.1% IDU was instilled into the eyes of patients with dendritic lesions, relief was noted within 12 to 24 hours after initiation of therapy. By 72 hours, marked healing of the epithelium occurred. IDU is highly effective in treating infectious corneal epithelial herpetic disease but is ineffective in herpetic-induced iritis, stromal keratitis, and other forms of HSV intraocular infection.^22,24 It is also less effective than trifluridine and vidarabine if topical corticosteroids are being used concomitantly.^25,26

IDU use has diminished with the advent of newer, more convenient drugs and is no longer commercially marketed. Recommended therapy when used is 0.1% q1–2h daily and 0.5% IDU ointment HS for 14 days.

RESISTANCE

HSV resistance to IDU is through modification of the thymidine kinase (TK) gene. Clinically resistant virus strains isolated from patients or created by serial passage through IDU-containing medium all had the common finding of reduced TK activity, sometimes as low as 5.6% of that of the wild-type or parental strain.^27,28 IDU-resistant HSV showed cross-resistance to BVDU and acyclovir, intermediate resistance to trifluridine, and full sensitivity to vidarabine and ganciclovir.²⁶

STRUCTURE

Trifluridine (TFT; F₃T; trifluorothymidine) (5-trifluoromethyl-2'-deoxyuridine, 2'-deoxy-5-[trifluoromethyl] uridine) is a fluorinated pyrimidine nucleoside. Structurally, it is an analog of the deoxyribonucleoside thymidine and is virtually identical to IDU with the exception of three fluorine atoms attached to a methyl radical replacing the iodine.²⁹ (see Fig. 1C). As a pyrimidine nucleoside analog, trifluridine inhibits DNA viruses, and because of its structure it is incorporated into rapidly growing host cell types (e.g., bone marrow).

MECHANISM OF ACTION

Although the specific mechanism of trifluridine inhibition of active herpesvirus production is not entirely certain, its antiviral activity appears similar to that of IDU and results from the effect of the drug on viral DNA synthesis²⁹ (see Table 1).

Trifluridine can exert its inhibition at several stages in the viral biosynthetic pathway leading from 2-deoxyuridine-5'-monophosphate to DNA synthesis. Trifluridine acts as a competitive inhibitor of thymidine.³⁰ The drug is initially phosphorylated to trifluridine monophosphate (TFT-MP), which is a potent inhibitor of thymidylate synthetase.³¹ Following phosphorylation to the triphosphate form (TFTTP), the compound competitively inhibits incorporation of thymidine triphosphate into viral DNA.

TOXICITY

Trifluridine is cytotoxic, teratogenic, mutagenic, and potentially carcinogenic and is sufficiently toxic that it is not used systemically.^32,33

In vivo treatment of normal rabbit corneas with trifluridine caused no adverse effects or evidence of corneal toxicity.³⁴ However, when rabbit corneas with standardized epithelial defects were treated with either 1% of 0.1% trifluridine drops eight times a day for 8 days, pathologic changes in the regenerating epithelium were observed. Stromal wound healing appears to be affected by trifluridine therapy (tensile strength was significantly reduced 12 days after wounding and treatment with 1% trifluridine).³⁵

PENETRATION STUDIES AND PHARMACOKINETICS

The biphasic solubility profile of trifluridine enhances the transport of the intact active drug across the cornea. The mechanism of penetration (as for IDU and vidarabine) appears to be by nonfacilitated diffusion demonstrated by linear penetration kinetics through excised, perfused rabbit corneas and the lack of demonstrable saturation kinetics.³⁶ Trifluridine penetrates the corneal epithelium more rapidly than IDU and vidarabine. The presence or absence of an intact epithelial cell layer did not significantly alter trifluridine's distribution. However, the concentration of trifluridine in the aqueous was increased in debrided or damaged corneas, and the rate of penetration was doubled.³⁷ Trifluridine (1%, four times a day) administered to both infected rabbit eyes and the eyes of patients with a history of recurrent herpetic keratitis penetrated the corneal stroma and achieved therapeutic levels (5–18 μg/mL).^36,38

The parent compound of trifluridine is hydrolyzed to 5-carboxy-2'-deoxyuridine within 3 to 5 hours at 37°C and pH 7.2.^37,39,40 This metabolite has little or no antiviral activity. In vivo, trifluridine is hydrolyzed to 5-carboxyuracil or to 5-carboxyuridine with the loss of the inorganic fluoride. The rate of elimination correlates with the rate of trifluridine metabolism. Monophosphate, diphosphate, and triphosphate metabolites of trifluridine are found in body tissues. The short serum half-life and toxicity of trifluridine (12–30 min) prevent the use of this drug in systemic herpetic infections.

EFFICACY

Trifluridine not only interferes with the replication of HSV-1 and HSV-2 but also has an effect on vaccinia and certain adenoviruses.⁴¹ Trifluridine (0.2–1.7 g/mL) inhibits the cytopathic effects of HSV-1 by 50% in plaque reduction assay.⁴² Plaque formation was reduced by over 98% when HSV-1 grown into Vero cells was treated with 17 μg/mL trifluridine.⁴³ Trifluridine activity in vitro is comparable to that of IDU, and trifluridine is considerably more active on a weight-for-weight basis than is vidarabine. As observed for both IDU and vidarabine, the strain of HSV-1 appears to be of major importance in determining the relative antiviral efficacy. Trifluridine was shown to inhibit five strains of HSV-1 within a narrow range; however, the susceptibility of five HSV-2 strains was variable, with two strains being insensitive at the maximum nontoxic concentration.⁴⁴

Trifluridine concentrations of 0.01 to 10 μg/mL administered as topical eye drops to experimentally infected rabbit corneas reduced the severity of the corneal herpetic ulcers when compared with saline-treated controls.²² Trifluridine was more potent on a weight-for-weight basis than IDU in the treatment of McKrae strain–induced HSV-1 herpetic keratitis, and when trifluridine and IDU were compared with respect to their ability to eradicate virus from the preocular tear film, no virus was recovered on days 2 and 4 of the 7-day treatment with trifluridine. However, HSV-1 was present in IDU-treated eyes throughout the treatment regimen.^22,45 Two days following discontinuation of therapy, rebound virus shedding had occurred in both groups, with virus titers higher than those observed in control, placebo-treated animals. These results indicate that a critical time period exists in an acute herpetic infection, during which time continued presence of the antiviral agent is necessary to control rebound virus shedding, even though infectious virus cannot be detected in the tear film.

Clinical studies comparing topical 1% trifluridine to 0.1% IDU, 3% vidarabine, or 3% acyclovir have shown that, overall, the latter two drugs and trifluridine have efficacy rates between 90% and 95% regardless of whether steroids are in use.^7,26,46–49 IDU efficacy was about 76%, dragged down by apparently less efficacy because of corticosteroid use in some patients or perhaps by its having been in clinical use so long that certain organisms had become resistant or patients had become allergic to the agent. Although trifluridine had a slight edge over all other drugs in the face of concomitant corticosteroid therapy, no statistical difference could be shown.

RESISTANCE

Resistance to trifluridine is rare and is discussed on the section on IDU⁵⁰

STRUCTURE

Vidarabine (9-β-D-arabinofuranosyladenine, ara-A) is a purine arabanosyl nucleoside structurally similar to deoxyguanosine⁵¹ (see Fig. 1 D and E).

MECHANISM OF ACTION

Vidarabine is not virucidal nor does it prevent attachment or penetration of infectious virus particles into host cells. Like all current antivirals it is virostatic (see Table 1). Its biologic activity is due in part to intracellular phosphorylation, first to the monophosphate (Ara-A-MP) form and subsequently to diphosphate and triphosphate (Ara-A-DP, Ara-A-TP) forms by cellular enzymes. Vidarabine inhibits viral DNA synthesis by several mechanisms. Direct incorporation into DNA as Ara-A-MP results in DNA chain termination. The triphosphorylated form, Ara A-TP, inhibits terminal deoxynucleotidyl transferase and DNA polymerase (α and β). Ara-A-DP and Ara-A-TP also inhibit the activity of ribonucleotide reductase enzymes.^52–54

TOXICITY

Following systemic or topical administration, vidarabine is converted to a hypoxanthine arabinoside derivative (ara-HX); this metabolite has only 20% of the antiviral potency of the parent compound.⁵⁵ The toxicity of vidarabine, administered systemically or topically, is negligible over a wide range of pharmacologic dosages. A major problem in systemic administration is that the compound's relative insolubility requires the use of large volumes of fluid, which can tax cardiovascular and renal homeostatic mechanisms. The drug is also teratogenic and mutagenic and has carcinogenic potential.⁵⁶ Thus, vidarabine is used systemically only as an alternative to acyclovir or ganciclovir in HSV or VZV drug-resistant, life-threatening situations.

Vidarabine administered topically to rabbits did not impair wound healing as measured by planimetry and histopathologic examination. However, stromal wound strength of vidarabine- or IDU-topically treated corneas was less than that of wounds treated with placebo ointment.¹⁶

PENETRATION AND PHARMACOKINETICS

Ocular penetration studies have shown that topically applied vidarabine crosses the cornea in minor amounts in corneas with intact epithelium. The deaminated semiactive metabolite Ara-HX was found in the aqueous in significant amounts following topical vidarabine treatment.^17,37 Application of 3% vidarabine in a water-miscible cream produced corneal levels of 20 μg/mL, whereas the same concentration in petrolatum ointment produced levels of only 4.5 μg/mL. Subconjunctival injection in dosages of either 25 or 100 mg resulted in intraocular Ara-HX titers of 6.5 μg/mL and 8.0 μg/mL, respectively.^57,58 No significant difference in aqueous Ara-HX concentration was observed among eyes receiving 25 or 100 mg vidarabine.

Following intravenous administration, vidarabine is rapidly deaminated by adenosine deaminase to the less effective Ara-HX form or other noneffective metabolites. Plasma levels of ara-HX are directly related to the rate of infusion. Plasma half-life is approximately 3.5 hours, and the metabolite Ara-HX is well distributed in tissues. Erythrocyte levels of Ara-HX are equal to plasma levels. Ara-HX readily crosses the blood-brain barrier and attains concentrations within 35% of plasma levels in the cerebrospinal fluid.^55,59 To enhance the antiviral efficacy of vidarabine therapy, potent inhibitors of adenosine deaminase that stop the conversion of Ara-A to Ara-HX have been used. These inhibitors have enhanced both the cytopathic and the cytotoxic activity of vidarabine in vitro.^60,61 Systemic administration of these compounds reduced vidarabine deamination (i.e., increased parent nucleoside concentration), increased cellular adenosine triphosphate (ATP) concentrations, and increased the virucidal activity by 20-fold, but also enhanced the cytotoxicity of these drugs.

EFFICACY

Vidarabine has a broad antiviral spectrum that includes many DNA viruses (HSV-1, HSV-2, VZV, CMV, vaccinia, and pseudorabies virus); it has little or no effect against RNA viruses.⁶² Plaque reduction assays using several different herpesvirus strains indicated a high degree of strain variability. As is the case with IDU, the cell type, virus passage, and virus strain all significantly affect the antiviral activity. Vidarabine is highly effective against IDU-resistant HSV-1 and HSV-2 in vitro.⁶³

In the eye, topical vidarabine 3% ointment has been found effective in herpetic keratitis and keratouveitis in both animal models and in humans.^{25,46,47,64,65} In one study of 69 patients with external ocular herpetic keratitis, vidarabine proved to be equal to IDU in reducing tear-film viral titers and in promoting corneal reepithelialization.⁶⁶ Vidarabine was significantly less toxic than IDU and caused healing of herpetic lesions clinically resistant to IDU. Other studies in patients with extensive dendritogeographic ulcerations substantiate these findings.⁶⁶ Fewer treatment failures occurred with vidarabine (9.5%) compared with IDU (18.8%) in a study of more than 300 ocular herpes patients.²⁵ Several studies referenced in this section and in the section on trifluridine indicate that there is no statistically significant difference between topical vidarabine, trifluridine, and acyclovir therapy for HSV ^46,47,49,67

Systemic vidarabine has been effective in therapy for varicella and for herpes zoster ophthalmicus, although it is now in a far fourth place behind valaciclovir, famciclovir, and acyclovir in this regard. Vidarabine therapy (10 mg/kg/day for 5 days) for varicella in immunocompromised patients reduced fever duration, lesion count, and systemic morbidity significantly compared to placebo⁶⁸ and resulted in more rapid cessation of viral shedding and increased healing rate of lesions.⁶⁸ Post-herpetic neuralgia could not be evaluated. Its role in TK-negative, acyclovir-resistant HSV mutants continues to make this a drug of interest.^3,70–72

RESISTANCE

Resistance to vidarabine appears related to viral DNA polymerase rather than to TK. Mutant, vidarabine-resistant viruses with changes in the DNA polymerase gene have been isolated.^73,74 This resistance was mapped to an 0.8 kb region within the pol gene and makes viral DNA polymerase less susceptible to Ara-A-TP.^73,75 Although other gene products may be affected, most HSV mutations have been found to code for the carboxyl-terminal portion of the viral DNA polymerase.⁷⁶ Such DNA polymerase mutation is of clinical significance because mutant HSV is resistant not only to vidarabine but also to the other common agents that use this antiviral mechanism. Resistance to vidarabine is uncommon and is discussed with reference to its use in place of HSV and VZV resistant to other antivirals (e.g., IDU, acyclovir).

STRUCTURE

Acyclovir (ACV; acycloguanosine) (9-[2-hydroxyethoxymethyl]guanine) is a synthetic compound that was designed to mimic substrates for model enzyme systems. Acyclovir is an analog of guanosine or deoxyguanosine in which the 2'- and 3'-carbon atoms are missing (see Fig. 1F). Acyclovir was the first compound engineered to have selective in vitro and in vivo antiviral activity.^42,77

MECHANISM OF ACTION

The major modes of action of acyclovir are viral DNA chain termination and rapid inactivation of viral DNA polymerase. Acyclovir is phosphorylated (activated) to acyclovir monophosphate (ACV-MP) specifically by herpesvirus-encoded thymidine kinase, thereby largely bypassing activation in any but infected cells^42,77 (see Table 1). This markedly reduces toxicity and increases specificity. ACV-MP is further phosphorylated to acyclovir diphosphate and triphosphate by viral and cellular enzymes. Acyclovir triphosphate (ACVTP) competes for deoxyguanosine triphosphate (dGTP), the natural substrate for virus-specific DNA polymerase and is incorporated irreversibly as ACVMP onto the growing viral DNA chains, thus causing chain termination.^78,79 Termination occurs because the acyclovir lacks the 3' hydroxyl group needed to react with incoming nucleotides. DNA polymerase then binds irreversibly to the acyclovir-terminated chain, and the entire enzyme complex is metabolically inactive. Little to no inactivation of cellular polymerase occurs.^42,78–80 Elion and co-workers have determined that ACVTP inhibits HSV DNA polymerase (DNA nucleotidyl transferase) ten to 30 times more efficiently than cellular DNA polymerase, another factor in reducing toxicity.⁷⁷ Approximately a 3000-fold concentration increase (above that which is virucidal) is needed to inhibit host cell growth.

TOXICITY

Since acyclovir is activated specifically by herpesvirus-coded TK, it was anticipated that the drug would be relatively nontoxic. Following corneal application of 3% acyclovir ointment, no toxic corneal effects were noted, and the quality and rate of re-epithelialization and stromal wound strength of the cornea were not impaired.¹⁶ Clinical study did note rare diffuse punctate keratitis that cleared following discontinuation of acyclovir therapy, but this apparent toxicity was thought to be a function of the drug vehicle.⁶⁵

The only important metabolite of acyclovir is 9-carboxymethoxy-methyl guanine (CMMG), an inactive compound that accounts for up to 14% of acyclovir dosage administered to humans.⁸¹ Renal clearance of acyclovir ranges from 75% to 80% of the total body clearance and is substantially greater than the clearance of creatinine, indicating that glomerular filtration and tubular secretion mechanisms (possibly the organic acid secretory system) are involved.⁸² The drug may rarely cause renal failure when given in high dose (>5 mg/kg) intravenously if there is renal insufficiency or dehydration. Hydration of all patients should be monitored and patients with renal insufficiency should have reduced doses and prolongation of the intervals between dosing to minimize this risk. Rare central nervous system toxicity, delerium tremens, and coma have been reported.⁸³ Other common side effects are gastrointestinal distress and headache. There is no evidence that acyclovir is a carcinogen or teratogen, and at therapeutic doses, there is no effect on the hematopoietic or immune systems.⁸⁴

PENETRATION AND PHARMACOKINETICS

Acyclovir can be administered safely and effectively by intravenous or subconjunctival injection, orally, or topically. Its adsorption following oral administration is variable and appears to be species dependent.^81,84–86 Animal studies have indicated that following oral administration in mice, 50% of the acyclovir is absorbed, and peak plasma concentrations occur 2 to 4 hours following ingestion.⁸²

In humans, oral absorption of acyclovir is incomplete, with bioavailability of the drug ranging between 15% and 30% of the dosage.⁸⁷ Peak plasma concentrations occur 1.5 to 2.5 hours following administration, and steady-state plasma concentrations following multiple oral doses of 2.5, 5, 10, and 15 mg/kg administered every 8 hours were 6.7 μg/mL, 9.7 μg/mL, 20 μg/mL and 20.6 μg/mL, respectively. These values are similar to the peak plasma concentrations observed following equivalent single oral doses, and acyclovir does not accumulate in plasma following repetitive dosing. Oral dosing of 200 mg q4h reaches steady-state levels ranging from 1.4 to 4.0 μM, which is inhibitory for HSV-1 and HSV-2; however, doses of 800 mg 5 times per day are needed to yield peak and trough serum levels, respectively, of 6.9 μM and 3.5 μM to inhibit most strains of VZV.^88–90

Studies on the concentrations of acyclovir in the tear film and aqueous in patients on receiving doses of 400 mg 5 times daily showed levels of 3.28 μM (0.96–8.79 μM) and 3.26 μM (1.10–5.39 μM), respectively, four hours after the last oral dose.^91,92 The mean ED₅₀ (effective dose reducing viral plaque count in tissue culture by 50%) of HSV-1 ranges from 0.15 to 0.18 μM and 0.1 to 1.6 μM, repectively, for the tear and aqueous levels, which indicated that the levels achieved were well in excess of that which should be needed to eliminate the virus.^8,88,91–93 This is not always the case. Stromal HSV particles may persist in the face of prolonged, therapeutic doses of oral acyclovir.⁹⁴ Drug resistance may have played a role in this finding. In comparison to HSV, the inhibitory doses for VZV are much higher at 3 to 4 μM, resulting in the need for fourfold higher drug dosing, as noted above, and less leeway in terms of resistance.⁹³

Following topical instillation of 3% acyclovir ointment in the inferior cul-de-sac of 25 eyes (every 5 hours for four to six doses prior to cataract extraction), the mean acyclovir concentration in the aqueous humor was 1.7 μg/mL, which falls within the therapeutic range.⁹⁵ Cutaneous adsorption of acyclovir may occur through damaged skin, but systemic adsorption is limited.

Total body distribution of intravenous ¹⁴C-acyclovir has been studied in several animal species.⁸⁶ Acyclovir rapidly enters all tissues following administration in both mice and rats. In humans with normal kidney function the serum half-life is about 3 hours. Intravenous dosing of 5 mg/kg three times daily results in serum ID₅₀ levels (inhibitory dose reducing viral plaque count in tissue culture by 50%), well above that needed for HSV-1 and HSV-2 at all times; however, dosage of 10 mg/kg three times daily was necessary to avoid trough levels that fell below the ID₅₀ of several VZV strains.^86,88,96,97 Multidose intravenous therapy with 400 mg to 1200 mg/M² every 8 hours resulted in acyclovir concentrations in kidney, lung, and brain that were 1000%, 131%, and 25% to 70% of plasma levels, respectively.⁹⁸ Cerebrospinal fluid (CSF) acyclovir levels were approximately 50% of corresponding plasma levels. The rapid penetration of acyclovir into the CSF has made this drug an important compound for treating focal and disseminated central nervous system herpetic infections.

Intravitreal acyclovir levels in humans 2 hours after administering13 mg/kg intravenously were at inhibitory levels for HSV-1 and HSV-2, VZV, and EBV.¹⁴⁷ Regular dosing of 5 mg/kg three times daily yielded concentrations of 8.8 to 11.0 μM, well in excess of the inhibitory dose for HSV-1 and HSV-2, VZV, and EBV, as did 25 mg of subconjunctival acyclovir.⁹⁹

EFFICACY

In vitro studies have demonstrated that acyclovir has a broad antiviral spectrum, including HSV-1 and HSV-2, VZV, EBV, and, to a lesser extent, CMV. Acyclovir is 160 times more potent than vidarabine and ten times more potent than IDU.^100,101 The inhibitory doses for various viruses have been noted previously.

Acyclovir (100 μg/mL) has been used in a drug-induced suppression model of HSV-1 infection in trigeminal ganglion cells. In this system, it produces a suppressed HSV-1 infection that is functionally identical to HSV-1 latency in vivo. Acyclovir has also been shown to suppress the reactivation of latent virus in explanted trigeminal ganglia.¹⁰² Latency was not eradicated, however, as demonstrated by an increase in viral titer following acyclovir removal. The rabbit eye model of HSV-1 infection has been used extensively to assess the in vivo efficacy of acyclovir.^103,104

Acyclovir is used for the following conditions:^{3,97,105–107}

1. primary genital HSV (oral or IV)
   
2. recurrent genital HSV in immunocompetent patients (oral)
   
3. mucocutaneous HSV in immunocompromised patients (oral or IV)
   
4. HSV encephalitis (IV)
   
5. neonatal HSV (IV)
   
6. varicella in immunocompetent (oral) or immunocompromised patients (IV then oral)
   
7. Herpes zoster in immunocompetent (oral) or immunocompromised patients (IV then oral)
   
8. Possibly EBV infections (oral)
   

Multiple clinical studies on infectious HSV epithelial keratitis comparing topical 3% acyclovir with 3% vidarabine ointment, 0.1% IDU drops, or 1.0% trifluridine drops in recommended doses revealed no statistically significant difference among the four drugs, although there was a trend suggesting that acyclovir was superior to IDU if concomitant corticosteroids were given. Acyclovir ophthalmic ointment is not commercially available in the U.S., although it is marketed in other countries.^{1,49,65,89–91,108–111}

Oral acyclovir 400 mg five times daily is equivalent to topical acyclovir in treating HSV epithelial keratitis, with ulcers healed in 90% of patients in a mean of 5 days.^91,112 Oral acyclovir 200 mg 5 times daily healed 95% of patients with combined HSV epithelial and stromal keratitis in 5 to 21 days.¹¹³ The therapeutic pediatric dosage is 20 to 40 mg/kg/day for 7 to 14 days as a pediatric elixir (200 mg/tsp).¹¹⁴ The early data on efficacy of oral acyclovir in stromal HSV is variable, with some encouraging and some negative studies reported.

Between 1994 and 2000, seven multicenter studies on the efficacy of oral acyclovir and/or topical corticosteroids on various forms of ocular HSV were reported from the Herpetic Eye Disease Study (HEDS).^115–121 The results may be briefly summarized as follows:

1. There was no statistically significant benefit from oral acyclovir 400 mg 5 times daily for 10 weeks in treating patients with HSV stromal keratitis who were already on corticosteroids and trifluridine.
   
2. Steroids were significantly better than placebo in resolving stromal keratitis; postponing steroids slowed resolution but made no difference in outcome by six months.
   
3. Treatment of patients with iritis who were already on corticosteroids and trifluridine with oral acyclovir 400 mg five times daily for 10 weeks may possibly have had some beneficial effect.
   
4. A three-week course of oral acyclovir 400 mg five times daily for treatment of patients with epithelial keratitis who were already on trifluridine did not alter the subsequent incidence of stromal keratitis or iritis.
   
5. After resolution of any form of ocular HSV, treatment for 1 year with oral acyclovir 400 mg bid significantly reduced recurrence of herpetic disease during that time and was without rebound up to 6 months after acyclovir therapy was stopped.
   
6. Oral acyclovir 400 mg bid for 1 year significantly reduced the recurrence of HSV stromal or epithelial keratitis, with greatest benefit in the stromal keratitis group.
   
7. Previous stromal, but not epithelial, keratitis markedly increased the risk of recurrent stromal disease in the future.
   

There are additional indications for oral acyclovir in patients with herpetic keratitis. These include use as an adjunct to topical antivirals in patients with atopic disease or in immunosuppressed patients, especially AIDS patients.^{1–3,121–123} Oral or intravenous therapy is determined on the basis of severity of immunosuppression in AIDS and similarly ill patients.¹⁰⁶ Dosage in atopy of 400 mg orally three to four times daily 2 to 3 weeks is generally quite effective. Another indication is use in those patients who are unable or unwilling to take topical antiviral agents for epithelial keratitis, such as patients with crippling arthritis, children or uncooperative adults, those whose occupation makes topical agents difficult to use, and those with ocular toxic medicamentosa from local antivirals. Adult dosage is 400 mg orally three times daily; for children it is 20 to 40 mg/kg in a divided dose for 10 to 14 days.

Prophylaxis of HSV epithelial recurrences in post-HSV keratoplasty patients with oral acyclovir is effective. A number of studies report significant efficacy in protecting grafts from recurrent HSV, the direct cause of failure in about 15% of cases.^124–127 The generally recommended dosage is 400 mg orally twice daily for 12 to 18 months post-keratoplasty. These findings are in agreement with those noted for long-term prophylaxis of recurrent genital HSV, including return to pretreatment recurrence pattern with cessation of therapy.^105,106

The role of oral acyclovir in zoster ophthalmicus is now well-established.^{89,90,128–130} In immunocompetent patients, oral acyclovir 800 mg 5 times daily for 7 to14 days (average, 10 days) results in more rapid resolution of viral shedding, acute neuralgia, and new skin lesions and reduced incidence of pseudodendritiform keratopathy, stromal keratitis, and iritis. There was variable effect on postherpetic neuralgia, depending on the study, and no effect on corneal hypesthesia or neurotrophic ulceration. With the exception of zoster-associated pain, acyclovir compares favorably with famciclovir and valaciclovir. In the presence of immunosuppression when zoster tends to be more severe and slow to respond to therapy initial treatment with IV acyclovir is indicated (1500 mg/m²/d in 3 divided doses = 10–15 mg/kg q 8 h) for 7–10 days followed by oral acyclovir 800 mg 5 times daily for 6–14 weeks. This dose is similar to that used in acute retinal necrosis.^{3,106,131–133}

RESISTANCE

An important consideration in the use of TK-activated antivirals is the development of resistant HSV strains. In vitro studies have shown that acyclovir resistance can be manifested by (1) a lack of viral thymidine kinase TK (2) altered substrate specificity of viral thymidine kinase such that it phosporylates thymidine but not acyclovir, and (3) a viral DNA polymerase gene mutation to alter the enzyme such that it is not inhibited by ACVTP. By far the most common mechanism of resistance is TK^minus mutation.^3,97

It has been suggested that acyclovir-resistant mutants might be less virulent than normal HSV-1 strains. Conflicting results have been obtained with acyclovir-resistant HSV-1 mutants in ocular studies. In rabbits, no difference was obtained with respect to viral pathogenicity or virulence between the parent HSV-1 virus and a thymidine kinase-negative mutation. In addition, HSV-1 mutants with altered substrate specificity retained the same level of virulence as the parent strains.¹³⁴ When the acyclovir-resistant virus was used in the mouse ocular model, the resistant virus had developed greater virulence with more associated neurologic deaths and tended to cause more severe stromal disease than did the parent acyclovir-sensitive virus.^135–138

Acyclovir-resistant HSV and VZV mutants are rarely seen in immunocompetent patients, but resistant strains are being encountered ever more frequently in immunodeficient patients.¹³⁹ The AIDS epidemic has accelerated this because of the large numbers of patients on long-term acyclovir therapy. Despite the TK^minus status of most mutants, severe mucocutaneous disease may result. Vidarabine and foscarnet are reasonable alternative drugs, as they do not require TK for activation.^139,140 An acyclovir-sensitive HSV strain with normal TK activity was isolated from a keratoplasty patient 3 weeks postoperatively¹⁴¹; 5 and 7 days later, as the clinical course deteriorated, acyclovir-resistant HSV with deficient TK activity was isolated. Despite sensitivity to foscarnet the graft eventually failed.

STRUCTURE

Valacyclovir is the L-valine ester of acyclovir (see Fig 1G). This prodrug was synthesized to enhance the oral absorbtion of acyclovir from the gastrointestinal tract. It undergoes an almost complete first-pass conversion to acyclovir and l-valine via enzymatic hydrolysis. The bioavailability of acyclovir is enhanced three to five times via this prodrug and is not altered by the simultaneous administration of food after enzymatic conversion to acyclovir.^142–145

A one-gram dose of valacyclovir gives peak plasma concentrations of 5 to 6 μg/mL of acyclovir, a therapeutic dose for both HSV and VZV. A daily dose of 1 g of oral valacyclovir gives a concentration-time curve of acyclovir similar to the intravenous administration of 5 mg/kg of body weight of acyclovir every 8 hours.¹⁴³

MECHANISM OF ACTION

After enzymatic conversion to acyclovir, the mechanism of action of valacyclovir is identical to that of acyclovir.

TOXICITY

In general, toxicity is negligible and patient tolerance is excellent.¹⁴⁶ Carcinogenicity, tumorigenicity, fertility, and mutagenicity studies on valacyclovir were negative.¹⁴³ Although acyclovir does cross the placenta, it was found that the rate of birth defects in infants of women on acyclovir during pregnancy was the same as the general population. The registry of patients studied was too small to evaluate to make definitive conclusions about the safety of the drug in the fetus.

Valacyclovir does, however, have a potential significant toxicity in immunosuppressed patients. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome has been reported in bone marrow or renal transplant or HIV-positive patients who were taking high doses of valacyclovir for prolonged periods of time. This drug is, therefore, not indicated in immunocompromised patients. There have been no such adverse reports in immunocompetent patients.^2,143

PENETRATION AND PHARMACOKINETICS

The pharmacodynamics of valacyclovir are similar to those of acyclovir.^147,148 Acyclovir is widely distributed throughout all body organs and fluids including the brain, CSF, vaginal mucosa, uterus, seminal and herpetic vesicular fluids, liver, and kidneys. Although there are no studies on the intraocular penetration of valacyclovir, drug titers are likely similar to or higher than those of acyclovir. Acyclovir concentrations after oral valacyclovir administration are about 50% of plasma levels. After multiple doses of 1 g of valacyclovir, these levels are 5 to 5.5 μg/mL. About 80% to 89% of drug is eliminated via the kidneys as acyclovir. Mean renal clearance of acyclovir exceeds creatinine clearance, indicating that renal tubular secretion is actively involved in elimination of drug, which is 99% acyclovir.^144,145,147

EFFICACY

Valacyclovir's antiviral activity, in descending order of in vitro susceptibility, is HSV-2, HSV-1 , VZV, EBV, human herpesviruses 6, 8, and 7, and CMV.^149–153

The primary clinical uses of valacyclovir approved by the U.S. Food and Drug Administration (FDA) are for treatment of herpes zoster and herpes simplex infections.^{144,148,154–156}

Clinical studies comparing oral valcyclovir 1.0 gm three times daily with oral acyclovir 800 mg five times daily in immunocompetent zoster patients indicated that the drugs were equivalent in ability to accelerate dermal healing and reduce the duration of virus shedding.¹⁵⁷ There was no difference if drugs were given for 7 or 14 days. Furthermore, studies on postherpetic neuralgia revealed that the median time to pain resolution was 38 days with valacyclovir and 51 days with acyclovir (p < 0.03). Numerous subsequent studies support the major efficacy of valaciclovir in herpes zoster, particularly if started within 72 hours of rash onset. In addition to being as effective as oral acyclovir compared to placebo (i.e., more rapid resolution of rash, acute pain, and viral shedding), there was no significant difference between the two drugs in incidence of conjunctivitis, epithelial keratitis, and stromal keratitis. Additionally, valacyclovir was significantly more effective in reduction and severity of postherpetic neuralgia.^{128,130,158–160}

The currently recommended dosage regimen for acute zoster at any site is 1 g orally three times daily for 7 days. In studies on valacyclovir in treatment of initial genital HSV infection, dosage is 1 g three times daily for 10 days. For recurrent genital HSV infection, therapy is 500 mg orally three times daily for 5 days; for suppression of recurrent episodes, dosage is 1 g orally daily for up to 1 year.^143,144 The treatment or prevention of ocular disease follows these same dosage guidelines although there have not, as yet, been definitive clinical studies.

A more recent application for valacyclovir is the inhibition of ocular HSV reactivation after excimer laser keratectomy or laser-assisted in-situ keratomileusis (LASIK).^161,162 The effective dose in the experimental model was 150 mg/kg per day for 2 weeks.

RESISTANCE

The mechanism of resistance of herpesviruses, most commonly VZV, to valacyclovir is similar to that of acyclovir; the vast majority are TK-deficient.¹⁴⁷ Although VZV resistance emerging from valacyclovir treatment of immunocompetent patients is very rare, the incidence of acyclovir-resistant VZV in immunosuppressed patients is increasing. It is most common in HIV-positive individuals but occasionally seen in organ-transplant recipients.^136–138

STRUCTURE

Famciclovir is the orally bioavailable diacetyl ester of 6-deoxy-penciclovir (see Fig 1H and I). Penciclovir is an acyclic guanine derivative similar to acyclovir in structure, mechanism of action, and antiviral activity.

MECHANISM OF ACTION

Penciclovir and acyclovir differ qualitatively in rates of phosphorylation, concentration of the triphosphate derivatives, stability, and affinity for viral DNA polymerase.¹⁶³ The intracellular activity of penciclovir is very long even when extracellular titers are low— 10 to 20 hours and 9 hours in HSV- and VZV-infected cells, respectively, compared to less than 1 hour for ACVTP in similarly infected cells.¹⁶⁴ Furthermore, penciclovir triphosphate (PCVTP), a nonobligate DNA chain terminator, is more effective than ACVTP, an obligate chain terminator, in inhibiting HSV DNA polymerase–mediated DNA chain elongation.^163,165

TOXICITY

Penciclovir's preferential phosporylation in herpesvirus-infected cells far exceeds that of acyclovir, but the minimal phosphorylation of penciclovir in uninfected cells and the low level of activity of PCVTP against cellular DNA polymerases explains the lack of toxicity of penciclovir and its derivative famciclovir in cell culture and in clincial studies.^166,167 In masked studies, there was no significant difference in adverse experiences such as headaches, nausea, and diarrhea between zoster and genital herpes patients receiving oral famciclovir or placebo for up to 18 weeks. Laboratory abnormalities in hematology, clinical chemistries, semen analyses, and urinalyses, were similar in both famciclovir and placebo groups.^168,169

PENETRATION AND PHARMACOKINETICS

Although penciclovir is very poorly absorbed from the gastrointestinal tract, famciclovir has an absorbtion rate of 77% after oral administration. The metabolite, penciclovir, is not further broken down but eliminated unchanged in the urine with a half-life of about 2 hours after IV administration.^166,167,170 Intracellular PCVTP activity persists despite low extracellular titers.

EFFICACY

Famciclovir is used for treatment of herpes zoster infection at dosages of 500 to 750 mg per day for 7 to 14 days. Famciclovir's efficacy is similar to that of acyclovir. In vitro activity includes HSV-1, HSV-2, VZV, and Epstein-Barr virus. Penciclovir's in vitro activity against VZV equals that of acyclovir with a mean EC₅₀ in tissue culture of 3 to 4 μg/mL.¹⁶⁷ In experimental HSV keratitis in rabbits, oral famciclovir twice daily at doses of 60 to 500 mg/kg of body weight, regardless of dose, resulted in significant reduction in keratitis and HSV-1 genomes in the trigeminal ganglion,as well as improved survival. This data suggests that oral famciclovir may reduce the morbidity of HSV in clinical situations.¹⁷¹

Clinical studies in several hundred immunocompetent non-ophthalmic zoster patients were quite successful. Oral famciclovir, 500 mg three times daily was compared to patients receiving placebo or acyclovir 800 mg five times per day for 7 days.^172–176 Results were clearly superior to those with placebo, and both drugs were similar in both stopping viral shedding and accelerating dermal healing. Perhaps more important, famciclovir had a significantly greater effect on reduction of postherpetic neuralgia compared to placebo or acyclovir. With an incidence of just over 50% in all groups, the median time to resolution of the neuralgia was 55 and 62 days, respectively, in the famciclovir and acyclovir groups compared to 128 days in the placebo group. These are also more favorable data on post-herpetic neuralgia (PHN) than that seen in acyclovir treated patients.

In a randomized, double-masked study on 454 patients comparing oral famciclovir 500 mg three times daily with oral acyclovir 800 mg five times daily revealed that both drugs were equally effective in all parameters of ocular disease. The effects on neuralgia were not reported.

RESISTANCE

No cases of resistance to famiciclovir or penciclovir have been reported.

STRUCTURE

Ganciclovir (DHPG; GCV) (9-[1,3-dihydroxy-2-propoxy]methylguanine) was the first of the five currently FDA-approved agents for treatment of CMV retinitis in immunosuppressed patients. This nucleoside analogue of deoxyguanosine is similar in structure to acyclovir with the addition of a terminal hydroxymethyl group in the acyclic sugar¹⁷⁷ (see Fig. 1J). The active form is gancliclovir-5'-triphosphate (DHPGTP).

CMV, however, does not code for viral TK. Viral sensitivity to ganciclovir is, therefore, not fully understood. Cellular kinases probably phosporylate some DHPG to its monophosphate.^178,179 It is also thought that CMV may induce a deoxyguanosine kinase which does initiate phosporylation of ganciclovir. Ganciclovir di- and triphosphates are then formed under the action of cellular guanylate and phosphoglycerate kinases. DHPGrTP levels are ten times higher than those of CVTP in CMV-infected cells, and they persist intracellularly for very long periods after drug has been removed. DHPGTP appears to serve as a deficient substrate and inhibitor of CMV DNA polymerase, with host cell polymerases being much less sensitive. Incorporation of DHPGTP into CMV DNA with subsequent chain termination plays some role, but because the effect is reversible, CMV DNA production begins again upon removal of the virostatic drug.¹⁸⁰

TOXICITY

Ganciclovir is essentially not metabolized by the body, and its clearance is dependent upon the kidneys. Although plasma levels and half-life increase with reduced renal function, the drug is not nephrotoxic. Toxicity is primarily hematopoietic, with neutropenia and thrombocytopenia, usually reversible, occurring in approximately 40% and 20% of patients, respectively, and often obviating use or limiting dosage of other myelosuppressive agents such as trimethoprim-sulfa, amphotericin B, and zidovudine; however, it may be used with other anti-HIV dideoxynucleotides.^180,181 Different immuno-suppressed groups reported with dose-limiting hematologic suppression; neutropenia is seen more frequently in AIDS patients, and thrombocytopenia is seen in patients immunosuppressed due to other causes. Other, less frequent side effects include nausea, neurotoxicity, hepatic dysfunction, fever, and local rash or phlebitis (DHPG = pH 11). Ganciclovir is carcinogenic and teratogenic and induces azoospermia.³

PENETRATION AND PHARMACOKINETICS

Ganciclovir's oral bioavailability is quite poor, less than 3%, necessitating IV administration. Fortunately, the ED₅₀ for most CMV infection is under 5 μM, which is readily achieved with IV dosing of 2.5- to 5.0 mg/kg.^183,184 The induction dose is 5 mg/kg IV q12h for 14 days; the maintenance dose is 5 mg/kg per day IV. Both achieve the mean ED₅₀of most CMV clinical isolates (5 μM, range 0.04–11 μM] in plasma, aqueous, and subretinal fluid. With a half-life elimination of 3 to 4 hours, it is widely distributed throughout body tissues and fluids.^184–186 Oral ganciclovir is available for clinical use, but its poor bioavailability (6%–9%) and the development of valganciclovir have greatly curtailed its use.¹⁸⁷

EFFICACY

Although ganciclovir is as active as acyclovir against HSV-1, HSV-2, VZV, and EBV, given its toxic nature it is used only in life-or vision-threatening CMV infections. It is 10 to 25 times more active against CMV than is acyclovir.^180,188 Significant clinical improvement occurs with ganciclovir therapy of nonocular CMV infections such as colitis, wasting syndrome and possibly pneumonia, and it is effective as prophylaxis in bone-marrow transplant patients.¹⁸¹

Ocular use is confined to CMV retinitis in immunosuppressed patients. Induction therapy is 5 mg/kg IV q12h, which results in regression of CMV retinitis in 81% to 100% of cases within 10 to14 days; however, there is a 30% to 50% breakthrough of maintenance therapy within 2 to 7 months, usually due to inadequate levels of ganciclovir relative to the patient's immune status. Oral dosage is three to four 250-mg capsules per day for maintenance therapy and prevention. New lesions at the edge of preexisting disease are the usual hallmarks of progressive or recurrent infection. Reinduction IV therapy is usually effective.^185,188,189 An additional problem is lack of therapeutic effect on foveal or optic disc disease. Because ganciclovir is virostatic and does not effectively eliminate CMV from the retina, viral DNA synthesis resumes upon removal of the drug, and disease recurs in up to 100% of chronically immunosuppressed patients.

Multiple intravitreal injections of 200 to 400 μg (vitreous levels > ID₅₀ HCMV at least 62 hours post-injection [not FDA-approved]) or high-dose 2000-μg injections weekly for up to 24 weeks are effective as local therapy in controlling the retinitis.^190–192 A high dose does not appear to cause toxicity, and prolonged remission suggests that higher-dose injections may be superior to lower doses.

An intraocular sustained-release device (Vitrasert) is an effective alternative therapy in myelosuppressed patients.^193,194 The surgically placed implant contains 4.5 mg of drug and releases ganciclovir at 1 μg per hour for 8 months before exchange is necessary. In general, the therapeutic response is very good and the complication rate low. Patients failing on more than 5 mg/kg twice daily of preimplant IV ganciclovir or more than 25% of the retina involved had the highest risk of treatment failure.^195–198

RESISTANCE

Ganciclovir-resistant CMV strains have been isolated in up to 27% of retinitis patients receiving treatment for 9 months or longer.¹⁹⁹ The mutation giving resistance to ganciclovir is in either the UL97 or the UL54 gene. Genotypically resistant viruses developed increasing phenotypic resistance with time and continued therapy. Change in therapy may allow a shift in virus population and the identification of the CMV genotype. Cidofovir, foscarnet, and vidarabine are alternative options in the face of ganciclovir resistance.

Ganciclovir has notable potential as a topical anti-HSV agent. Clinical trials have shown that 0.15% ganciclovir gel or 3% acyclovir ointment five to three times/day over 1 week was therapeutically equivalent, but that ganciclovir had superior local tolerance.²⁰⁰

STRUCTURE

Valganciclovir is a prodrug of ganciclovir developed to increase the oral bioavailability of ganciclovir and to achieve a plasma level comparable to that achieved with IV ganciclovir. Valganciclovir is a monovalyl ester of ganciclovir that is rapidly hydrolyzed to ganciclovir by intracelllular esterases in the mucosal cell of the gut and by hepatic esterases^201,202 (see Fig. 1K).

MECHANISM OF ACTION

Because of valganciclovir's rapid hydrolysis to ganciclovir by gut and hepatic esterases, the pharmacodynamics are those of ganciclovir.²⁰³ Anti-CMV activity of ganciclovir is via inhibition of viral DNA synthesis by ganciclovir triphosphate, which competes with deoxyguanosine triphosphate (dGTP) as a substrate for DNA polymerase. This plus incorporation of ganciclovir triphosphate into the DNA chain stops viral replication.

TOXICITY

Because valganciclovir is virtually ganciclovir after its rapid hydrolysis to the lattert, the toxicity and tolerability profiles are similar. The use of induction therapy was studied in random open trials using either oral valganciclovir 900 mg twice daily for 3 weeks, and then 900 mg daily for 1 week, or IV ganciclovir 5 mg/kg twice daily for 3 weeks, and then 5 mg/kg once daily for 1 week.^202,204 Both drugs had similar tolerability except for catheter-related infections in the ganciclovir group. Adverse side effects were similar in incidence in both groups and included, in decreasing order of incidence (16%–8%), diarrhea, neutropenia, nausea, headache, and anemia. In a separate study, 252 from the original group continued the regimen of oral valganciclovir 900 mg daily for 9 to 36 months. Again, the most common side effects were intestinal and hematologic; there was also an increase in serum creatinine (τ15 mg/L) in 15% of recipients.²⁰⁴

PENETRATION AND PHARMACOKINETICS

Ganciclovir is about 26 times more potent than acyclovir, the former having a mean IC₅₀ of 2.7 μmol/L. The drug also inhibits the immune responses associated with CMV infection.²⁰³

The absolute bioavailability of ganciclovir from valganciclovir is 10 times higher than from oral ganciclovir.^205,206 The mean bioavailability of a single 1-g dose of oral ganciclovir was 5.6% compared to 60.9% for a single 360-mg dose of valganciclovir.²⁰⁵ A dose of 2625 mg once daily for 3 days in recently fed patients produced ganciclovir plasma levels of 0.6 mg/L at 1 to 1½ hours. Plasma levels then fell below measurable levels by 4 to 6 hours.²⁰⁷ Gastrointestinal absorption is notably better with food in the stomach than in the fasting state.

Oral valganciclovir 900 mg once daily achieves plasma levels comparable to an IV dose of DHPG of 5 mg/kg in CMV-positive, HIV-positive, and liver transplant patients.^206,207 Oral valganciclovir 900 mg once daily for 3 days with food resulted in a target ganciclovir level (41 mg/L at one hour) similar to that of patients receiving IV ganciclovir 5 mg/kg per day). The elimination half-life of oral valganciclovir is about 3.5 hours; that of oral ganciclovir 1000 mg is 7 hours.²⁰⁵

EFFICACY

Like ganciclovir, its hydrolyzed form, valganciclovir is as active as acyclovir against HSV-1, HSV-2, VZV, and EBV. Because of its potential toxicity, it is used only in life- or vision-threatening CMV infections, both for active disease and prophylactically as maintenance. Because once-daily oral valganciclovir 900 mg produces a daily exposure dose comparable to 5 mg/kg IV ganciclovir, this prodrug may be more suitable in many circumstances currently requiring IV ganciclovir, allowing far more convenience and reliability in dosing of patients with CMV retinitis, using a 2- or 4-tablet regimen daily to cover all phases of therapy.

The induction dose is oral 900 mg/kg twice daily for 21 days; maintenance dose is 900 mg/kg daily. It is likely that oral valganciclovir will replace ganciclovir in the majority of cases needing such treatment.

RESISTANCE

A small number of ganciclovir-resistant strains have been recovered from HIV-positive and CMV-positive patients.²⁰¹ The resistance appears to come from point mutations in a gene encoding a protein kinase involved in phosphorylation of ganciclovir as well as one encoding viral DNA polymerase.

STRUCTURE

Cidofovir (CDV; HPMPC) ( [S]-9-[3-hydroxy-2-phosphonylmethoxypropylcytosine) is an acyclic nucleotide analogue derived from phosphonoformic acid. It is currently used in combination with probenecid for treatment of CMV retinitis in HIV-positive patients^208,209 (see Fig. 1L) and may have a role in HIV-negative immunosuppressed patients.

MECHANISM OF ACTION

Cidofovir does not require activation by viral-encoded TK, and phosphorylation of cidofovir is independent of virus infection. The mechanism of action is through cidofovir diphosphate (CDVDP), which inhibits viral DNA polymerase at concentrations 50-fold lower than the level that inhibits cellular polymerases.²¹⁰ The decreased rate of viral DNA synthesis is due to incorporation of cidofovir into the growing viral DNA chain (see Table 1). Cidofovir resists degradation by esterases and persists intracellularly for up to 65 hours. This may allow drug-carrying cells to resist replication for several days when challenged by virus after therapy has been discontinued.²¹¹

TOXICITY

Cidofovir is carcinogenic in rats and potentially so in humans. At 65 times the recommended dose it causes chromosomal alterations in red blood cells in vitro. It inhibits spermatogenesis and is embryotoxic in laboratory animals.²¹² Pediatric use should be with caution because of the drug's carcinogenic and reproductive toxicity.

The major dose-limiting toxicity of cidofovir is nephrotoxicity in 50% of patients on maintenance dose of 5 mg/kg body weight given every other week. There is early increase in serum creatinine and proteinuria, and later glucosuria, when proximal tubular damage occurs. Neutropenia occurs in 20% of patients on maintenance. Interestingly, ocular hypotony was noted in several patients on maintenance.²¹² Punctal stenosis has occurred in during topical use.

PENETRATION AND PHARMACOKINETICS

Pharmakokinetic studies in vitro show slow elimination with a half-life of 22 hours, which supports use of intermittent dosing to achieve efficacy while minimizing toxicity.²¹³ Protein-binding is minimal (< 6%), and the time to peak serum concentration is at the end of the infusion. Peak serum concentration with a 1-hour infusion of cidofovir 5 mg/kg body weight with probenecid is about 19 μg/mL. Approximately 70% of cidofovir is recovered unchanged in human urine within 24 hours.²¹²

EFFICACY

Cidofovir is effective against many herpesviruses including HSV-1, HSV-2, VZV, EBV, ganciclovir-resistant and ganciclovir-sensitive CMV, as well as against several adenoviruses and vaccinia.^208,209,214 Comparison of topical 1% and 0.5% cidofovir with trifluridine and acyclovir in a rabbit HSV-1 keratitis model showed that both concentrations of cidofovir were significantly better than either of the other two drugs.^215,216

Cidofovir is an agent of current interest as a potential treatment for adenovirus and is effective in vitro against adenovirus types 1, 5, 8, and 19. In the rabbit model 0.5% cidofovir twice daily for 7 days showed significant efficacy against adenovirus types 1, 5, and 6, all important strains in epidemic forms of the ocular disease.^215,217

Because of its high in vivo potency and excellent therapeutic index, cidofovir is now used as a first-line drug against CMV retinitis, using either IV infusions (5 mg/kg once weekly for 2 weeks, and then low-dose (3 mg/kg) or high-dose (5 mg/kg) administration weekly.²¹⁸ Median time to progression of retinitis was 2.5 months, and median time to discontinuation of cidofovir because of intolerance was 6.6 months, with no difference between the two treatment groups. Treatment was effective, but monitoring for toxicity, which resolved with stopping the drug, was considered essential. Two notable ocular side effects were hypotony (3.8%) and nongranulomatous iritis, which occurred regardless of the route of administration, whether IV or intravitreal injection, and was related to drug, not disease.^219–221

Intravitreal cidofovir has also been successful in management of CMV retinitis, with doses ranging from 10 to 20 μg given every 5 to 6 weeks, in some cases up to ten injections.^219,222 It was concluded that intravitreal 20 μg cidofovir as initial and maintenance therapy was highly effective, with only rare episodes of progression; 10 μg was less effective but also less toxic.

Other successful regimens reported are combinations of 1 g three times daily of oral ganciclovir plus a ganciclovir-releasing implant versus IV cidofovir 5mg/kg once or other week. There was no significant difference between either group for controlling retinitis, preventing visual loss, and mortality. Simlarly, combined IV cidofovir every two weeks with oral ganciclovir 1 gm three times daily effectively controlled retinitis in seven patients over a span of 12 months.^223,224

RESISTANCE

In experimental adenoviral ocular infection in the rabbit model, treatment with 0.5% cidofovir twice daily for 7 days of known cidofovir-resistant strains showed no therapeutic effect compared to the parental adenovirus type 5 strain.²¹⁵ In CMV retinitis, clinical resistance to intravitreal cidofovir was found in 5% of patients and was asssociated with prior oral ganciclovir or IV cidofovir. Resistance-associated mutations were found in the UL97 and polymerase genes. Resistant CMV disease can result from a local infection independent of a systemic site of CMV infection.²²⁵

STRUCTURE

Foscarnet (PFA; phosphonoformic acid) is a pyrophosphate derivative of phosphonoacetic acid. It differs from the previously discussed antiviral agents in that it is not a nucleoside analog²²⁶ (see Fig. 1M). It is FDA-approved for treatment of CMV retinitis in immunosuppressed patients.

MECHANISM OF ACTION

Antiviral action is through a selective and noncompetitive inhibition of viral specific DNA polymerases and RNA polymerases (reverse transcriptases) at concentrations not affecting cellular polymerases²²⁷ (see Table 1). As the reaction is reversible, the drug is virostatic with viral replication restarting upon removal of the agent. Because foscarnet does not require phosporylation and directly affects the pyrophosphate binding site on viral polymerases, it is therapeutically useful against resistant TK^--herpesviruses. Because of its anti-viral reverse transcriptase effect, it has efficacy against HIV.^{8,70,71,227–229}

TOXICITY

Renal toxicity may occur in up to 45% of AIDS patients. with resulting azotemia and the need for constant monitoring of creatinine levels in all patients on the drug.^230,231 Foscarnet is excreted unmetabolized by renal tubular secretion and glomerular filtration. Toxicity may be due, in part, to interference with renal phosphate secretion.^226,232 This nephrotoxicity may be avoided or minimized in many cases by using intermittent dosing rather than constant infusion and by maintaining excellent patient hydration. Elevated creatinine levels almost invaraibly return to normal (if due to drug) within 2 to 4 weeks of reducing or ceasing administration. Electrolyte changes must be monitored bcause the serum calcium may become quite high or low, a problem in itself, and one which concomitant use of other drugs, such as pentamidine, which affect calcium balance, is precarious.²³³ Similarly, serum phosphorus and magnesium levels should be monitored.

Other toxic side effects include anemia in up to 50% of patients, hepatic enzyme elevation, central nervous system dysfunction, headaches, nausea and other gastrointestinal disturbances, mucous membrane erosions, and nephrogenic diabetes insipidus.^231,232 Neutropenia and thrombocytopenia are not seen with foscarnet therapy.

PENETRATION AND PHARMACOKINETICS

Oral absorption of foscarnet is very poor, resulting serum levels negligible, and gastrointestinal irritation common.²³² The intravenous induction dose at the recommended regimen of 60 mg/kg over 1 to 2 hours three times daily results in peak plasma levels above the ID₅₀ for most CMV (100–300 μM), HIV (132 μM), and HSV (100 μM) strains.^{71,226,230,232,234} CSF levels are 43% of plasma levels.²³⁵ The half-life is 4 hours, and no drug is detectable in the serum by 24 hours, having been cleared by the kidneys unmetabolized. Unlike other antivirals, part of the dose sequesters in the bone marrow for as long as several months.²¹⁴ Over a 7-day period, up to 20% of the administered dose may be deposited in the bone marrow of AIDS patients. This may be related to the calcium fluctuations seen in some patients.

EFFICACY

Foscarnet is effective against all known human herpesviruses, CMV, HSV-1, HSV-2, VZV, and EBV, and against the retrovirus HIV. The primary therapeutic indication is the treatment of CMV retinitis in immunosuppressed patients. Other indications include any systemic form of life-threatening CMV infection and acyclovir-resistant mucocutaneous HSV or VZV in immununocompromised patients.²³⁵ Doses of 60 mg/kg three times daily IV for 2 to 3 weeks and maintenance with 90 to 120 mg/kd per day are as effective as ganciclovir in CMV retinitis. Clinical response takes about 1 week.^{71,226,236,237} Because foscarnet does not need viral TK or other enzyme-dependant phosphorylation to be activated, it is also of use, and superior to vidarabine, in treatment of the acyclovir-resistant HSV and VZV infections most commonly seen in AIDS patients.^228,229

Ganciclovir and foscarnet are comparable against CMV retinitis, but survival time in the group initially treated with foscarnet was 12 months compared to only 8 months in the ganciclovir group.²³⁸ This may be due to the anti-HIV effects of foscarnet, suggesting that foscarnet may be a drug of choice for initial therapy. Unfortunately, foscarnet was more toxic than ganciclovir, with 20% of foscarnet patients switched to ganciclovir and only 2% of ganciclovir patients switched to foscarnet because of side effects. Foscarnet and ganciclovir may act synergistically, implying that clinical trials using each drug at lower doses may be therapeutically beneficial.²³⁹

In studies on combined foscarnet and ganciclovir vs monotherapy in 279 HIV-positive patients with active CMV, survival was similar in all three groups (∼8.5 months) but the time until CMV retinitis progression was significantly longer in the combination patients who could tolerate both drugs.²⁴⁰

Intravitreal injection of foscarnet is not FDA-approved but has been successful in healing CMV retinitis that recurred in five patients on full IV foscarnet maintenance therapy. The drug was given intravitreally to each patient at dosage of 2.4 μg/0.1 ml twice weekly for 3 weeks while maintaining IV foscarnet therapy. Four of the five patients healed after 3 weeks; the fifth patient developed intraocular infection after the fourth injection, and therapy was discontinued.²⁴¹

RESISTANCE

Recent reports of foscarnet-resistant HSV involved virus which was also acyclovir-resistant.²⁴² No relationship was found to the TK gene to explain the acyclovir resistance. Four patients had undergone allogeneic stem-cell transplantation.²⁴¹ One patient was cured with valacyclovir and two with cidofovir, but the fourth patient died despite cidofovir treatment. A leukemic child with HSV stomatitis responded well to a course of cidofovir.²⁴³ In the Studies of Ocular Complications of AIDS (SOCA) trials, drug-resistant CMV was found in half the ganciclovir-treated patients and no foscarnet patients with persistent viremia. All ganciclovir-resistant strains were from patients treated for a median of 7 months. The foscarnet patients were treated for a median of 5 months without development of resistant strains.²⁴⁴

STRUCTURE

Fomivirsen (ISIS 2922) is an antisense oligodeoxynucleotide made up of 21 phosphorothioate-linked nucleosides (see Fig. 1N). Antisense oligonucleotides are short, synthetic, single-stranded DNA or RNA sequences that are designed to target and bind messenger RNA (mRNA) thereby interfering with gene expression and inhibiting protein synthesis. Fomivirsen is the first drug in this class to be tested clincially in the treatment of CMV retinitis in HIV-positive patients.^195,245,246

MECHANISM OF ACTION

Fomivirsen binds to complementary sense sequences on mRNA transcribed from the major immediate-early transcriptional unit of CMV.²⁴⁷ The mechanism of action is at least twofold. One is the inhibition of CMV immediate-early gene expression, a sequence-dependant antisense mechanism essential for virus replication; the other is inhibition of viral adsorption to host cells, a sequence-independent mechanism.²⁴⁸ By blocking the function of mRNA units, fomivirsen drug can produce specific and potent blocking of CMV replication without interfering with human genes. In vitro, its efficacy is dose-dependent.

TOXICITY

Because fomivirsen is given only intravitreally, toxic side effects tend to be local. Ranging in incidence from 5 to 20% and dose-dependent, these include abnormal or blurred vision, color vision desaturation, subconjunctival bleeding, eye pain, floaters, retinal hemorrhage, edema or detachment, elevated intraocular pressure, anterior segment inflammation, cataract, vitreitis/uveitis, retinal pigment epithelial damage, and destruction of photoreceptors.²⁴⁹ The therapeutic index of fomivirsen, particularly for intraocular inflammation and irreversible retinal toxic reaction, is quite narrow, thus making it relatively harmless in some patients and causing notable damage in others.²⁵⁰

PENETRATION AND PHARMACOKINETICS

In the rabbit, 4 hours after intravitreal injection of 66 μg of fomivirsen, the mean drug concentration in the vitreous was 3.3 μmol/L. Elimination of drug was slow, with a half-life of 62 hours.²⁵¹ Ten days after drug injection the mean concentration of fomivirsen in the rabbit vitreous was still within the CMV inhibitory range.²⁴⁵ Of the drug detected at this time, 22% was intact fomivirsen and 78% was in the form of chain-shortened metabolites of the parent drug. This indicates marked drug metabolism within the vitreous cavity.

The elimination half-life from the monkey retina was 78 hours after a single 115-μg dose.²⁵² There was no accumulation of formivirsen in the vitreous of monkeys after multiple weekly or biweekly doses of up to 115 μg. There was, however, accumulation of drug in the retina after multiple doses of 57 μg per week and 115 μg every 2 weeks, indicating that clearance mechanisms may have been saturated by multiple injections.

EFFICACY

Fomivirsen intravitreal injections are indicated for the treatment of CMV retinitis in HIV-positive patients who are unresponsive or intolerant of other anti-CMV therapy.²⁴⁹ In clinical trials in which 165 μg of fomivirsen was administered once a weeks for 3 weeks, followed by 165 μg every 2 weeks maintenance, it was found that the time before HIV-positive patients with newly diagnosed peripheral CMV retinitis experienced progression of disease was significantly longer than for similar patients in whom treatment was deferred until disease progression had occurred (median time to progression, 71 days vs 14 days, respectively).²⁴⁴ In separate studies of previously treated patients, there was a significant delay in disease progression in 54 patients with advanced vision-threatening CMV retinitis when treated with fomivirsen 330 μg weekly for 3 weeks, and then every 2 weeks as maintenance or with the same dose on days 1 and 15 and monthly maintenance.²⁵³ Clinical response (decreased border opacification) was noted at a median of 8 days after initiation of treatment, and median time to disease progression was 90 days in both treatment groups.

Current recommended treatment is induction therapy with intravitreal injection of 330 μg (0.33 mg) every other week for two doses, and then maintenance with intravitreal injection of 330 μg monthly.

RESISTANCE

Because fomivirsen's mechanism of action is different from that of other inhibitors of CMV that inhibit viral DNA polymerase, this antisense drug has been found effective therapeutically against CMV isolates that are resistant to ganciclovir, foscarnet, and/or cidofovir. Resistance to fomivirsen itself has been created in vitro by selective isolation of CMV clones increasingly less sensitive to the drug than to the parent virus.^249,250 To date, no fomivirsen-resistant clinical isolates have been reported.

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