SURVEY OF OPHTHALMOLOGY

VOLUME 37 - NUMBER 1 -JULY-AUGUST

THERAPEUTIC

REVIEW,

1992

JOEL MINDEL, EDITOR

Systemic Antiviral Drugs Used in Ophthalmology STEVEN A. TEICH, M.D.,’ TONY W. CHEUNG,

M.D.,2 AND ALAN H. FRIEDMAN, M.D.’

Departments of ‘Ophthalmology and 21nternal Medicine, Mount Sinai School of Medicine, New York, New York Abstract. Over the past two decades, the recognition of viral enzymes and proteins that can serve as molecular targets of drugs has revolutionized the treatment of viral infections. Beginning with acyclovir, a number of systemically administered agents which are both relatively safe and effective for the treatment of herpetic infections and human immunodeliciency virus (HIV) infections have become widely available. Because of increased numbers of herpes virus infections, as well as the rising epidemic of HIV infections, the ophthalmologist is, more likely than ever before to be involved in the treatment of severe and frequent ocular infections caused by herpes viruses. In addition, the acute retinal necrosis (ARN) syndrome has been demonstrated to be caused by herpes viruses and a once rare retinal infection caused by cytomegalovirus is common in patients with the acquired immunodeficiency syndrome (AIDS). In this article, four systemic antiviral drugs (Vidarabine, Acyclovir, Ganciclovir, and Foscarnet) that have demonstrated usefulness in the treatment of ophthalmic disease are reviewed in detail with regard to their mechanisms, applications, effectiveness, and side effects. (SLUT Ophthalmol %7:19-53, 1992) acquired immune deficiency syndrome Key words. antiviral drugs conjunctivitis cytomegalovirus keratitis retinitis uveitis l

l

l

l

l

acute retinal necrosis herpes viruses HIV l

l

l

l

Antiviral chemotherapy has lagged behind the development of antibiotics for bacterial infections. This is, ironically, related to the simplicity of viruses. Bacteria, because they are relatively complex self-replicating organisms, have many metabolic differences from mammalian cells that can be selectively attacked by drugs. Viruses are much more primitive. As obligatory intracellular parasites, they replicate only by invading a cell and utilizing the host’s biochemical mechanisms to synthesize new viral proteins and genetic material. Therefore, it has been difficult to develop drugs that would inhibit viral functions without also damaging the host cell. Over the past two decades the recognition of viral enzymes and proteins that can serve as molecular targets for drugs has revolutionized the treatment of viral infections.x4 All currently available antiviral agents are virostatic and, therefore, an intact immune system is required to maintain the sup-

pression of many viral infections. Although topical ophthalmic therapy for herpes simplex virus (HSV) infections has been available since 1962 (i.e., idoxuridine, vidarabine, and trifluridine),2”gs’g~447 it is only in the past decade, with the advent of acyclovir, that there is relatively safe and effective systemic treatment of herpetic infections.375.43a Other systemically administered antiviral agents include vidarabine, ganciclovir, foscarnet, interferons, and zidovudine. The development of effective antiviral drugs is especially timely for the ophthalmologist, who is treating new herpetic retinal infections, such as the acute retinal necrosis syndrome,“’ and a variety of severe infections in the increasing population of patients with AIDS.sgl This review will focus on the ophthalmic uses of systemic antiviral agents. Topical ophthalmic antiviral agents that are too toxic for systemic use are beyond the scope of this review, and have 19

20

TEICH ET AL

Surv Ophthalmol 37 (1) July-August 1992

been reviewed elsewhere.30~s’7Tables 1 and 2 list the current ocular and systemic indications for the use of the systemic antiviral agents discussed herein, their recommended dosages, and their toxicities.

H2N

I. Vidarabine Vidarabine (9-beta-D-arabinosyladenine, adenine arabinoside, ara-A) was the first antiviral agent to be licensed for systemic use against lifethreatening viral infections, when its effectiveness was demonstrated in the treatment of HSV encephalitis. 456However, it is being replaced for this use by acyclovir, which is more effective, less toxic, and more easily administered.3g7*452 A. MECHANISM OF ACTION, COLOGY, AND TOXICITY

HOkH;!

A

B

NH2

P- P C-ONa Nao-r ONa

PI-IARMA-

Vidarabine is a purine nucleoside analog (Fig. 1) with in vitro activity against certain DNA viruses, including herpesviruses, poxviruses, and probably hepatitis B virus.g8*‘y8.“g3*yo5*45’ 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 herpes virus DNA, where it acts as a chain terminator. Unlike acyclovir, vidarabine does not require viral thymidine kinase for its phosphorylation.45’ Therefore, vidarabine might be expected to have activity against thymidine kinase deficient mutants of HSV.‘25*‘g2*253 However, since it does not selectively inhibit virally induced enzymes, there exists a potential for cellular toxicity, especially at high doses.45’ Vidarabine is rapidly deaminated to hypoxanthine arabinoside (Ara-Hx), which has much less About 50% of an intraveantiviral activity. 316,451 nous dose appears in the urine in 24 hours, mainly as Ara-Hx. 3g The dosage must therefore be lowered in the presence of renal dysfunction. A disadvantage of vidarabine is its poor solubility, which requires 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. Minimally effective aqueous humor levels of vidarabine and At-a-Hx were found after a few days of intravenous therapy at a dosage of 20 mg/kg per day in patients with herpes simplex keratouveitis.2 The currently recommended dosage is lo- 15 mg/kg daily for up to 10 days for life-threatening HSV infections. The major adverse reactions are gastrointestinal (anorexia, nausea, vomiting, and diarrhea)

OH

C

D

Fig. 1. Chemical structures of acyclovir (A), ganciclovir (B), Vidarabine (C), and Foscarnet (D).

and occur in lO-15% of patients.305*35gCentral nervous system disturbances occur in 2-10% and can be severe.305,35g~433*45’ Ocular flutter has been reported in an AIDS patient receiving vidarabine.“j3 Neurotoxicity is increased in the presence of renal dysfunction or when the drug is given in combination with either interferon3’j3 or the xanthine oxidase inhibitor, allopurinol (due to its inhibition of Ara-Hx metabolism).‘55 Elevations in serum bilirubin and aspartate may occur and hematologic toxicity occurs at higher dosages. 305Vidarabine is teratogenic in animals and must be used with extreme caution in women of child-bearing age.377 B. SYSTEMIC USES Vidarabine is beneficial in the treatment of herpes simplex encephalitis45” and in varicellazoster virus infections in immunosuppressed adults.455,457However, acyclovir is more effective and less toxic.38g*5g7,452 Vidarabine and acyclovir are equally effective for the management of neonatal HSV infections.453 Vidarabine is without proven benefit in the treatment of systemic cytomegalovirus (CMV) disease in neonates and renal transplant patients.5g*272*362 C. OPHTHALMIC Intravenous

USES

vidarabine

has a quite limited

SYSTEMIC ANTMRAL

DRUGS USED IN OPHTHALMOLOGY TABLE

21

1

Systemic Drugs and Recommended Dosages for Viral Infections Virus

Drug

Cytomegalovirus Retinitis

Foscarnet

Ganciclovir

Ganciclovir (investigational) Ganciclovir with or without immunol-globulins (investigational)

Colitis or esophagitis Pneumonitis Herpes simplex virus Epithelial keratitis

Stromal keratitis Prophylaxis after penetrating keratoplasty Genital

200-400 mg p.0. orally 5 times a day for 2 to 3 weeks.

Acyclovir

Primary: 200 mg p.0. 5 times per day for 10 days. Recurrence: 200 mg p.o. 5 times per day for 5 days. Chronic suppression: 400 mg p.o. bid or 200 mg p.o. tid for up to 1 year. IO mg/kg IV Q 8 hours for 10 to 21 days. As for adults. 15 mg/kg/day IV over 12 to 24 hours for IO days. 5 mg/kg IV Q 8 hours or 400 mg p.o. 5 times a day for 7 days. 40 mg/kg IV Q 8 hours for 7 days.

(adults)

Acyclovir

Encephalitis

(neonatal)

Acyclovir Vidarabine

in immunocom-

Acyclovir Foscarnet

Herpes zoster (Varicella-zoster virus) Varicella in immunocompromised

(investigational)

Acyclovir Foscarnet Acyclovir

(investigational)

Zoster in immunocompromised

Zoster ophthalmicus

Foscarnet Acyclovir

(investigational)

in normals

Acute retinal necrosis (due to VZV, HSV-1 or HSV-2)

Human immunodeftciency virus-1 AIDS, ARC, OR CD4 ~500

Acyclovir

Zidovudine

Interferon

Optimal dosage unknown, Optimal dosage unknown.

500 mg/m* IV Q 8 hours for 7 days. 40 mg/kg IV Q 8 hours. lo-12 mg/kg IV Q 8 hours for 7 days. 40 mg/kg IV Q 8 hours. 800 mg p.o. 5 times a day for 7 to 10 days 500 mg/m’ IV Q 8 hours for 7 to 10 days. May be followed by p.o. Acyclovir 800 mg 5 times a day for 4 to 14 weeks. 100 mg p.o. 5 to 6 times per day (some suggest 200 mg Q 4h fat CNS disease). 125-300 mg p.o. bid.

DDI Papillom4zvirus Condyloma acuminata

60 mg/kg IV Q 8 hours for 14 days (induction), then 90-120 mg/kg 7 days per week (maintenance) 5 mg/kg IV BID for 14 to 21 days (induction), then 5 mg/kg 7 days per week or 6 mg/kg 5 days per week (maintenance). As for retinitis. As for retinitis.

Acyclovir (investigational for use in those unable to use topical agents. Trifluridine, vidarabine, or idoxuridine are preferred) Acyclovir (investigational) Acyclovir (investigational)

Encephalitis

Mucocutaneous promised

Dosage

alfa 2-b

1 million units/O.1 ml intralesional injection in up to 5 warts 3 times/week for 3 weeks. (Continued on next page)

22

Surv Ophthalmol 37 (1) July-August 1992

TEICH ET AL

TABLE 2

Toxicity of Systemic Antiviral Agents Agent Vidarabine

Acyclovir

Less Common

Common

Neurotoxicity (tremor, encephalopathy, ataxia, peripheral neuropathy, ocular flutter)

Gastrointestinal distress Bone marrow suppression Abnormal liver function tests Phlebitis Renal insufficiency Gastrointestinal distress Headache

Ganciclovir

Neutropenia Thrombocytopenia

Foscarnet

Renal insufficiency Proteinuria Serum calcium abnormalities Hypomagnesemia Anemia

Zidovudine

Anemia Neutropenia Headache Asthenia Dizziness Insomnia Anorexia Nausea & vomiting Malaise Myalgia Peripheral neuropathy Pancreatitis Headache insomnia Elevated serum uric acid Influenza-like syndrome (fever, chills, headache, myalgia, arthralgia) Nausea & vomiting Diarrhea

Didanosine (DDL)

Interferon

role in the treatment of ocular herpetic infections, both because of the effectiveness of topical agents in HSV cornea1 disease and because of the superiority and relative ease of administration of acyclovir when systemic treatment is required. Topical vidarabine 3% ointment was approved for the treatment of HSV epithelial keratitis in 1977, and its use has been reviewed extensively elsewhere.30~40~3’7*3’* Abel and associates2 felt that intravenous vidarabine gave slight improvement in HSV stromal keratouveitis, but there was no

Encephalopathy Nausea & vomiting Rash Urticaria Phlebitis Fever Rash Urticaria Phlebitis Abnormal liver function tests Confusion Serum phosphorus abnormalities Abnormal liver function tests Hallucinations Tremors Seizures Phlebitis Genital/penile ulcers Nephrogenic diabetes insipidus Toxic myopathy Aplastic bone marrow Nail discoloration Cystoid macular edema Hypertrichosis of eyelashes

Retinal pigment epithelium atrophy (children) Optic neuritis Bone marrow suppression Neurotoxicity (fatigue and depression) Weight loss Abnormal liver function tests Cardiotoxicity Hypertrichosis of eyelashes

longterm follow-up. Herpes simplex 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.428 An uncontrolled trial of intravenous vidarabine for CMV retinitis in seven pharmacologically immunosuppressed patients suggested some improvement in four. 335However, the beneficial effect was often transient, high doses (20 mg/kg) were required to suppress (but not eliminate)

SYSTEMIC ANTMRAL

DRUGS USED IN OPHTHALMOLOGY

urinary viral excretion, and there were serious associated gastrointestinal, hematologic, and neurologic side effects.“3’ Treatment could not, therefore, be generally recommended. A case of disseminated VZV with bilateral retinitis, consistent with 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.“” It appears, therefore, that vidarabine’s role is that of a “back-up” drug for serious HSV and VZV infections should resistance to more effective and safe drugs occur.“’

II. Acyclovir Acyclovir (9-[2-hydroxyethoxymethyl] guanine) has proved to be an extremely safe and effective agent and is the drug of choice for most forms of HSV and VZV infections. Its availability in topical, oral, and intravenous preparations allows its use in a wide range of clinical situations. A. MECHANISM OF ACTION, PHARMACOLOGY, AND TOXICITY An acyclic analog of guanosine (Fig. l), 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.“” The drug inhibits, in order of decreasing effect, HSV types I and 2, VZV, and Epstein-Barr virus (EBV), but not human cytomegalovirus.x5~“76 Its in vitro activity is 160 times greater than that of vidarabine.“75 Acyclovir’s antiviral spectrum is, however, limited to the herpes group and excludes vaccinia, adenoviruses, and RNA viruses.“‘” Acyclovir is inactive and must be phosphorylated to the nucleotide form, acyclovir triphosphate, in order to exert its antiviral activity. The drug 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.“’ Acyclovir triphosphate is found in HSV infected cells at concentrations 40-100 times greater than in uninfected cells.“” 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 an ID,,* similar *The reports cited in this review use the terms “IDs,l” (inhibitory dose) or “EDso” (effective dose) to indicate the drug concentration required to obtain a 50% reduction in plaque number of viral infected cells in culture.

23

to that of the host’s cellss5 Acyclovir triphosphate is both an inhibitor of, and a substrate for, viral DNA polymerase. Enzyme activity is irreversibly also has a greater lost.‘5g Acyclovir triphosphate 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 J’hydroxyl group and, therefore, no attachment point for the next link. However, the fact that EBV, which does not produce herpesdirected thymidine kinase, is sensitive in vitro to acyclovir suggests that additional mechanisms of action may exist.“s’“54 Acyclovir can be administered topically, intravenously, and orally. The dosage is timed to achieve drug levels in the extracellular fluid that are greater than the ID,, for HSV types 1 and 2 (mean, 0.1 to 1.6 kM) and VZV (mean 3 to 4 Antiviral activity, however, is actually PM). 3*,85,‘07 due to intracellular levels of acyclovir triphosphate. With intravenous dosing, the serum halflife is about 3 hours in adults with normal renal function. At a dosage of 5 mg/kg body weight three times a day, serum concentrations are well above the ID,, for HSV 1 and 2, but trough levels fall below the ID,, of many VZV isolates.‘” However, a dosage of 10 mg/kg three times a day provides trough levels sufficient for most VZV infections. 15,‘07Acyclovir is 15% protein-bound and the volume of distribution is 70%, corresponding to total body water.“” The cerebrospinal fluid level is 50% that of plasma.““” Seventy percent of acyclovir is excreted unchanged in the urine through filtration and secretion.“” The dosage must be adjusted in the presence of renal failure. Acyclovir is readily hemodialyzable. ““.“’ Absorption of orally administered acyclovir is slow and incomplete with a bioavailability of 15-30%. Peak plasma levels are reached in 1.5-2 hours. Steady-state levels after 200 mg orally every 4 hours range from 1.4 FM to 4.0 FM (mean 2.5 PM).~“* While these levels are inhibitory for HSV types 1 and 2, they are near or below the ID,, of VZV. However, 800 mg orally five times a day yields peak and trough serum levels of 6.9 PM and 3.5kM, respectively, which should have a better clinical effect on VZV.“‘7.‘7”-“x’ Clinically significant intraocular concentrations of acyclovir are achieved following oral or intravenous administration. A dose of 400 mg orally five times a day produces tear7”” and aqueous”” acyclovir levels in excess of the ID,, of HSV type 1. The intravitreal acyclovir level two hours after an intravenous dose of 13 mg/kg was

1992

TEICH ET AL

within the therapeutic range of HSV types 1 and 2, VZV and EBV. ss’ Intravitreal concentrations of 8.8 to 11.0 ~J,.Mmay result from intravenous acyclovir dosages of 5 mg/kg three times a day.15 Subconjunctival injections of 25 mg in five eyes prior to enucleation resulted in clinically significant aqueous and vitreous levels.3”2All eyes, however, demonstrated subconjunctival crystals. Further studies are needed. In patients with the acute retinal necrosis syndrome (ARN), who received acyclovir in the infusion fluid during vitrectomy at doses of 10 Fg to 40 Kg, there was no evidence of retinal toxicity, but one patient developed a posterior subcapsular cataract.4g Acyclovir has been a remarkably safe drug. Toxic effects are predominantly associated with high doses (more than 5 mg/kg) of the intravenous formulation. 25 Since the pH of the intravenous formulation is 11, concentrated solutions are caustic. Local irritation, phlebitis, and vesicular lesions may result from subcutaneous infiltration.232*41sSuch reactions can be circumvented by infusing acyclovir at a concentration no greater than 6 mg/ml.14 Acyclovir’s major adverse effect is on renal function, due to crystallization and deposition of the drug in the kidneys of patients who are dehydrated or have preexisting renal insufficiency. 36 Renal dysfunction can be avoided by infusing acyclovir slowly over one hour and administering 1 liter of fluid with each gram of the drug. I4 Oral acyclovir has, rarely, been associated with renal dysfunction’n” Nausea, vomiting, and abdominal pain can occur, and probably represent a direct toxic effect on the gastrointestinal tract.25 There is one report of diarrhea, presumably caused by the presence of lactose in oral acyclovir tablets, which responded to oral lactase administration.266 Rare case reports suggest a relation between acyclovir use and central nervous system toxicity or psychiatric disturbances. These have occurred mainly in association with the use of other neurotoxic agents or in the presence of renal disease."~66~"3a,"4a~39'~424~"'~yper_

safety in pregnant women or in neonates has not been established.“’

24

Surv Ophthalmol

37 (1) July-August

sensitivity reactions, typically transient maculopapular rashes near infusion sites, occur in less Since acyclovir can be inthan 1% of patientsI corporated into DNA, there has been some concern over its possible mutagenicity. There is no significant evidence that acyclovir is a carcinogen.6’*42” While at much higher than clinically relevant doses acyclovir has been teratogenic in animals,238 other animal studies indicate that it is not a significant teratogen.‘07s2g8 Despite the lack of concrete evidence indicating teratogenicity in humans, the drug does cross the placenta and its

B. SYSTEMIC

USES

Acyclovir is less toxic and more efficacious than vidarabine in the treatment of HSV encephalitis.3g7*452 The usual dosage for HSV encephalitis is 10 mg/kg every 8 hours for at least 10-14 days.435 Comparable activity has been found with vidarabine and acyclovir in the treatment of neonatal HSV infections, 16’ but acyclovir 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.38’s’.2g4~306*453 Oral and intravenous treatment are superior to topical treatment.*’ Oral acyclovir is only modestly effective in treating genital or orolabial HSV recurrences in immunocompetent adults.28s,407 However, in patients with frequently recurring genital herpes, chronic oral acyclovir reduces the frequency of recurrences. Doses of 400 mg twice daily are convenient and well-tolerated.22s~2s7 Unfortunately, following completion of acyclovir therapy, patients may return to their previous pattern of recurrent infection. Systemic acyclovir in various regimens has been used successfully for both the prevention and treatment of mucocutaneous HSV infections in immunosuppressed patients.‘08~‘65~263~28’~348*373* 374,3go*4’2,442 However, recurrences commonly occur following the cessation of therapy. The benefit of acyclovir for VZV infections is established in immunocompromised patients when given intravenously at a dosage of lo-12 mg/kg every 8 hours. ",2',24,'35.327.389,990 The clinical usefulness of acyclovir in the treatment of varicella-zoster virus infections in immunocompetent adults and children with nonophthalmic disease is less clear. In adults several studies have found intravenous acyclovir to be beneficial when administered within 72 to 96 hours of the onset of symptoms.24,327,464Oral acyclovir, at a dosage of 400 mg five times a day, is clinically ineffective in VZV infections in immunocompetent patients.203~27g However, higher dosages of 600-800 mg five times a day have been of some benefit when initiated within 48-72 hours of exanthem and are of proven efficacy in treating herpes zoster ophthalmicus (HZO).43,44, 63*64.203,464 Recent studies have suggested that high-dose oral acyclovir given within 24 hours of exanthem can reduce the severity and duration of primary varicella infections (chickenpox) in

SYSTEMIC ANTMRAL

DRUGS USED IN OPHTHALMOLOGY

normal children22~“3 and adults.‘34 It is not known how this might affect the subsequent risk of herpes zoster. Prophylactic high-dose intravenous or oral acyclovir may reduce the likelihood and severity of CMV infections in CMV seronegative renal and CMV seropositive bone-marrow transplant recipients.‘8,2g’ Despite the absence of a CMVderived thymidine kinase, sufficient cellular phosphorylation of acyclovir may occur in these patients. Trials of acyclovir in the treatment of established CMV infections, on the other hand, have shown no consistent benefit in immunosuppressed

patient~.20~'01~333~438~440

In acute systemic EBV infections (or infectious mononucleosis) acyclovir temporarily suppresses oropharyngeal EBV replication and excretion. The slight clinical benefit is, however, not considered to justify the routine use of acyclovir in this condition.‘,49’ High-dose oral acyclovir can cause regression of EBV-induced oral hairy leukoplakia in HIV-infected patients.‘5fi,350 The lesions recur when therapy is discontinued. The experimental agent desciclovir, a prodrug which is converted to acyclovir by xanthine oxidase following oral absorption,243 has also caused regression of oral hairy leukoplakia.“’ C. OPHTHALMIC 1. Herpes

Simplex

USES Virus

Although not commercially available in the U.S.A., topical acyclovir in a 3% ointment is as effective as trifluridine in the treatment of HSV epithelial keratitis,247.24” and can penetrate the cornea to reach the anterior chamber.334 Oral acyclovir, in a dosage of 400 mg five times a day, is more effective than a placebo*“* and equivalent to topical acyclovir. 75,77 in the treatment of herpes simplex dendritic ulceration. This dose of oral acyclovir results in aqueous205 and tear fluid leve1s75,77 above the ID,, of HSV type I. Collum and coworkers” reported that 90% of their orally treated patients had healing of dendritic ulcers in a median of five days. In another study 200 mg five times a day healed epithelial keratitis within 5-2 1 days in 18 of 19 patients with concomitant stromal keratitis or uveitis.“x4 In most cases of HSV epithelial keratitis a topical antiviral drug, such as trifluridine, would be preferable to a systemic agent. However, although not approved for this use, oral acyclovir may be considered in certain situations.“’ An oral agent might be more effective in young children, the elderly, the disabled, or others in whom using an eyedrop is difficult or impossible. It could also be a useful

25

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.270 Prophylactic oral acyclovir after penetrating keratoplasty in herpetically infected patients has potential for preventing HSV reactivation during postoperative corticosteroid therapy.“’ Although acyclovir cannot eliminate ganglionic latency, it might reduce viral shedding in this high-risk

situation,29~'0'.'2'~"8."'0.4'5

and

in a rabbit

model it significantly lowers the incidence of keratitis.‘g In three eczematoid patients with HSV epithelial, stromal, or uveal disease who were undergoing penetrating keratoplasty or cataract extraction, Schwabsa4 used prophylactic acyclovir 200 mg orally live times a day for 14-2 1 days followed by tapering to 2-3 times daily. None experienced a recurrence of disease while remaining on therapy for up to 18 months. A randomized controlled trial is needed to verify the benefit of oral acyclovir for this indication. Another potential use for oral acyclovir is in the treatment of herpetic stromal disease andjor keratouveitis. Both active viral proliferation and immunogenic mechanisms appear to play important roles.45y Topical corticosteroids, which are required to suppress immunogenic mechanisms,76 may trigger or exacerbate viral replication.309,319,353 In general, topical antivirals have been disappointing in the treatment of stromal keratitis,459 although topical acyclovir with a topical corticosteroid may possibly be beneIicial.76,434 This has led to interest in the use of oral acyclovir. Various investigators, in small, uncontrolled studies, have reported a beneficial effect of systemic acyclovir with topical corticosteroids in treating HSV stromal keratouveitis.“‘.7”,‘37s4” On the other hand, Sanitato and associates”” found the combination of topical and oral acyclovir to be ineffective in the treatment of 17 patients with disciform edema or necrotizing stromal keratitis, who did not receive topical corticosteroids. As the authors point out, it is possible that at the dosage used (200 mg five times a day) subtherapeutic amounts of drug may have reached the stroma. Schwab”s4 used oral acyclovir 200 mg five times a day for 14-21 days with subsequent tapering in the treatment of 20 patients with active stromal keratitis or keratouveitis, who were not adequately controlled by topical corticosteroids and antivirals. AI1 improved while using oral acyclovir, although one patient relapsed when the drug was tapered and three of seven patients who discontinued acyclovir had prompt

26

Surv Ophthalmol

37 (1) July-August

1992

recurrences. In addition, of four patients with previously active HSV stromal keratitis treated prophylactically, only two could successfully discontinue topical corticosteroids and antivirals.3s4 Oral acyclovir is, therefore, a promising adjunct to the therapy of recalcitrant stromal or uveal disease caused by HSV. It does not, however, reduce the recurrence rate once treatment is discontinued.“‘7,384 It is not clear to what extent clinical improvement can be attributed to the stromal antiviral effect of acyclovir and to what extent it is due, secondarily, to resolution of steroid-enhanced epithelial infection. The relative role of oral acyclovir in conjunction with topical corticosteroids and antivirals, as well as the optimal dosage and duration of treatment, requires further elucidation. These issues are being evaluated in a controlled, multicenter clinical trial (the Herpetic Eye Disease Study) on the efficacy of oral acyclovir in the treatment of herpetic stroma1 keratitis and iridocyclitis in patients receiving topical corticosteroids.” Intravenous acyclovir has been used successfully to treat HSV retinitis in an otherwise healthy adult.176 HSV retinitis can also occur in immunosuppressed patients,3’3,42s and it may be difftcult to clinically distinguish from the more common CMV or VZV retinitis. If the clinical situation indicates a high probability of HSV or VZV retinitis and the lesions are not imminently vision-threatening, a trial of high-dose intravenous acyclovir may be attempted. If there is no response, then therapy with foscarnet or ganciclovir should be instituted.“’ 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.30’ 2. Herpes Zoster Ophthalmicus High doses of oral acyclovir (600-800 mg five times a day) have been found effective in reducing the ocular complications of keratitis and uveitis in herpes zoster ophthalmicus,43~63~ 64,‘80*‘g’awhich accounts for lo-25% of cases of zoster dermatitis.343 This represents a major therapeutic advance in a disease for which only palliation was previously available. Cobo et a163,64performed a placebo-controlled clinical trial in 71 immunocompetent patients with acute HZ0 presenting within one week of onset of skin lesions. They demonstrated that oral acyclovir, at a dose of 600 mg five times a day for ten days, ameliorated the cutaneous signs

TEICH ET AL 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 regardless of initial severity of disease. Patients did not receive oral or topical corticosteroids. Compared to placebo, oral acyclovir significantly reduced the incidence of pseudodendritiform keratopathy (from 3 1% to 14%), stromal keratitis (56% to 25%) and anterior uveitis (56% to 19%). There was no effect on episcleritis, nor on the development of cornea1 hypesthesia or neurotrophic ulceration. It was postulated that although the 600 mg dose was beneficial it may have been near the threshold for effect.62 Virus-productive disease did persist, as was evidenced by the development in some patients of new dermatomal lesions and skin microdissemination and the recovery of virus from skin lesions as late as 14 days.64 One could speculate that an 800 mg dose might have been even more beneficial, as it gives peak and trough serum levels above the ID,, of VZV and has been effective and well tolerated.203~280~281~464 Other investigators43,180,‘91” found that the 800 mg dose without corticosteroids for 7-14 days in immunocompetent patients with HZ0 prevented “severe” complications. Acyclovir has not yet been shown to prevent or control post-herpetic neuralgia. This complication is most common in those over the age of 604” and especially over 80.“’ Cobo et al,64 in a placebo-controlled trial, found no effect of the 600 mg dose on the incidence, severity, or duration of post-herpetic neuralgia.@ Wood et al464 found that acyclovir, 800 mg five times a day for seven days, had no effect on post-herpetic neuralgia. In two other placebo-controlled trials, the 800 mg dose given for ten days decreased postherpetic neuralgia at one to three months, but not at four to six months.‘80~203Although systemic corticosteroids have been advocated to prevent post-herpetic neuralgia,23’ a placebo-controlled study failed to demonstrate a benefit of adding prednisolone to acyclovir. 126 In summary, oral acyclovir therapy is indicated for all immunocompetent patients with herpes zoster ophthalmicus at a dosage of 800 mg five times a day for ten days.261 Whether this treatment prevents chronic life-disruptive postherpetic neuralgia cannot be answered definitely at this time. Herpes zoster infections may be more fre-

SYSTEMIC ANTIVIRAL DRUGS USED IN OPHTHALMOLOGY quent anu severe in immunosuppressed patients with an increased risk of cutaneous and visceral dissemination and of encephalomyelitis.“j This is especially important in patients with AIDS, or HIV seropositivity in whom HZ0 may be the first indication of underlying immunosuppression.6g,234*370 Intravenous acyclovir therapy”~“‘* p4~327~38g is beneficial in these patients. High-dose intravenous acyclovir has been recommended in high-risk patients with HZ0 prior to the results of HIV testing to prevent central nervous system 385 Oral acyclovir may also be complications. beneficial. We have successfully used oral acyclovir 800 mg five times a day for ten to 14 days to treat HIV infected patients with HZ0 who did not have severe disease and who were otherwise not sufficiently ill to require hospitalization. There is not, however, sufficient data to recomOne must be wary of mend this approach.‘” using oral acyclovir to treat AIDS patients with acute HZ0 because they may suffer from malabChronic keratitis can develop with sorption.*‘* HZ0 in AIDS, which may be poorly responsive to with systemic acyclovir. ‘*’ Retinitis in association HZ0 may also occur in AIDS patients.58.20g It can appear similar to the acute retinal necrosis syndrome, but the response to intravenous acyclovir treatment has been variable.‘47~20g~27’ 3. Acute Retinal Necrosis Syndrome The acute retinal necrosis syndrome (ARN) has been recently reviewed by Duker et al.“’ In view’of the evidence implicating VZV and HSV as etiologic agents, 37,58,86,87,'5',209.233,259,4'0acyclovir has been an attractive potential therapy. Pepose and Biron3** have determined the ED,, of VZV recovered from the vitreous of a patient with ARN (5.3 PM). These serum and vitreous levels are easily achievable with the current intravenous dosage of acyclovir for ARN,34,381 but are difficult to maintain with oral therapy.*” Acyclovir given intravenously (1500 mg/m’ per day in three divided doses) allows more rapid resolution of the retinitis,34*‘94~20g~277and has become the mainstay of therapy. Because this syndrome is relatively uncommon, a randomized placebo-controlled trial has not been performed. In the largest reported series of treated patients, Blumenkranz and associates34 used intravenous acyclovir in the above-mentioned dosage for 7-2 1 days with an average of about 10 days. The average dose was 945 mg every 8 hours. Regression began in about four days and was usually complete in approximately one month. Three of 13 eyes retained 20/30 or better vision and eight

27

could see 20/400 or better. No eye had visual loss due to progressive retinitis or optic neuropathy after two days of therapy and no patient had involvement of the second eye during acyclovir usage. A recent study has confirmed that in unilateral cases acyclovir reduces the risk of fellow eye involvement. 3” Despite acyclovir therapy, the progression of vitritis was common, implying immunologic processes at work. Unfortunately, acyclovir did not reduce the incidence of retinal detachment. 34 However, some believe that the use of acyclovir in the “mild type” of ARN may lessen the risk of retinal detachment.82~276*277 It appears reasonable, therefore, to treat ARN with intravenous acyclovir 1500 mg/m*/day in three divided doses (usually equivalent to between 10 and 15 mg/kg eight-hourly) for 7-l 0 days. It has been suggested that oral acyclovir (800 mg five times daily) be continued for 6-14 weeks after intravenous treatment, as this is the period of greatest risk of bilateral involvement.“‘.“” Aspirin and prednisone may be useful adjuncts.“v34s’’ ’ Prednisone should not be started until after acyclovir therapy has been initiated. ” ’ There is a report of successful acyclovir therapy ofARN without the use of systemic corticosteroids in an immunocompetent patient.‘” Recently, a rapidly progressive outer retinal necrosis, which is poorly responsive to acyclovir therapy, has been described in AIDS patients. Clinical and laboratory evidence is suggestive of a VZV retinal infection.‘47*27’ The use of early prophylactic vitrectomy with intravitreal infusion of acyclovir in doses of 1Okg to 4Opg, in addition to intravenous acyclovir, has given variable results.34*4g,328Although selected patients might benefit, this therapy cannot be recommended routinely.34 Although not approved for use during pregnancy,“’ one of us (AHF) has used intravenous acyclovir to treat a woman who developed ARN in her 9th month of gestation. There was a good response to therapy, which was initiated ten days prior to a cesarean section. The neonate was healthy with no apparent adverse effects from acyclovir. 4. Epstein-Barr Virus Both acute and chronic EBV infections have been associated with ocular inflammatory disease. '.P74a However, most of the evidence has been circumstantial.’ There have been only a few case reports of acyclovir use for presumed ophthalmic EBV infection. Cornea1 lesions and conjunctivitis resolved in one case of infectious mononucleosis treated with topical acyclovir.458

28

Surv Ophthalmol 37 (1) July-August 1992

TEICH ET AL

Fig. 2. Left: Cytomegalovirus (CMV) retinitis in a 33-year-old man with AIDS. Right: Eight weeks later there has been regression of the retinitis despite no antiviral treatment.

However, stromal keratitis associated with EBV infection has responded to topical corticosteroids without the use of acyclovir.275~330*33’*463 One patient had no recurrences of presumed EBV keratitis during or after six months of treatment with oral acyclovir, 330but this may represent the natural course of the disease. Wong et a1463reported 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. In one, intraocular inflammation improved 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 although the systemic symptoms acyclovir;‘“’ improved, there was no mention of the response of the 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. 5. Cytomegalovirus (CMV) There are no well documented cases of successful treatment of CMV retinitis with acyclovir. Although regression of CMV retinitis in AIDS patients has been reported with the use of acyclovir and zidovudine,‘33 this was felt to represent improved immunologic function caused by the anti-HIV effect of zidovudine on CD4 lymphocyte function. One of us (SAT) has seen spontaneous regression of CMV retinitis in an HIV

positive patient (Fig. 2) who was using no antiviral agents (although it subsequently recurred and required therapy with ganciclovir). Highdose intravenous acyclovir plus oral zidovudine was of dubious benefit in minimally delaying the recurrence of CMV retinitis in AIDS patients following successful induction with ganciclovir.386 D. 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.” 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, but are becoming more common in immunodefiThis is especially so in AIDS cient patients. 120~2’2 patients receiving chronic therapy with acycloAlthough many thy_ vir. 57,119.125,144,212.22’.2’3,364,472 midine kinase deficient HSV mutants appear less neurovirulent and less efficient in establishing ganglionic latency, I40 they may cause progressive and severe mucocutaneous disease in immunocompromised patients, especially with AIDS.57*‘25*‘g2P273 Some of these patients have been successfully treated with foscarnet which does not rely on phosphorylation by thymidine kinase.57,3”*472Continuous intravenous infusion

SYSTEMIC ANTMRAL

DRUGS USED IN OPHTHALMOLOGY

29

duce thymidine kinase and so will not readily phosphorylate acyclovir, but it is thought to induce a deoxyguanosine kinase which does monophosphorylate ganciclovir. Cellular kinases then convert this agent to the active triphosphate form.*‘” It is the much more efficient phosphorylation of ganciclovir, compared to acyclovir, in CMV infected cells that makes it a more effective agent against CMV. *‘* The efficacy of ganciclovir against other herpetic viruses is likely due to its phosphorylation by the same virus-encoded thymidine kinase that phosphorylates acyclovir.“” The intracellular phosphorylation of ganciclovir is relatively selective in that levels of ganciclovirtriphosphate within CMV-infected cells are ten times that inside uninfected cells. However, bone-marrow cells can be uniquely sensitive to ganciclovir,*‘” which explains why neutropenia is its greatest adverse effect. III. Ganciclovir Ganciclovir is poorly absorbed from the gastrointestinal tract and so at this time must be Ganciclovir (DHPB;S-[ 1,3-dihydroxy-2-propoxymethyl] guanine) is the first drug to be apgiven intravenously. The ED,, for most clinical proved by the FDA for use in the treatment of isolates of CMV is less than 5 I.LM and is easily CMV retinitis in immunocompromised patients. achieved with a 2.5 or 5 mg/kg intravenous dose.2”~256~532~406 Ganciclovir has a large volume of Although immunosuppressed patients also distribution and exhibits biexponential decay appear to derive some benefit from ganciclovir with a terminal elimination half-life of 3.60 for CMV infections of the lung and gastrointestinal tract, the evidence of ganciclovir eRicahours.40” It penetrates the cerebrospinal fluid cy for these infections is less clearcut.55~74~‘z4~“g~*22~ and achieves concentrations inhibitory to 256,274,388 CMV.2”~2”6 Intraocular, and specifically subretinal fluid levels, are above the ID,, for most CMV A. MECHANISM OF ACTION, PHARMAstrains and approach plasma levels.7’~2’0~‘67~38” COLOGY, AND TOXICITY Clearance of ganciclovir is dependent upon Ganciclovir is an acyclic nucleoside analogue renal elimination and is correlated with creatiof deoxyguanosine which differs from acyclovir nine clearance. It undergoes little or no metaboonly by the addition of a terminal hydroxylism. Its half-life and plasma levels are increased methyl group (Fig. 1). It is lo-25 times as active in the presence of renal insufficiency406 and, alas acyclovir against CMV and at least as active though not nephrotoxic, dosage reduction is against HSV 1 and 2, VZV, and EBV.7’*267,278, necessary in the presence of renal dysfunction. 401,423,427 As with acyclovir, the inhibition of viral Hemodialysis efficiently reduces ganciclovir replication is produced only by the triphosphate plasma levels by about 50%, which suggests that form of the drug. Although the mechanism of the drug should be administered after dialysis.406 action is not completely understood, ganciclovir Despite the poor oral bioavailability of ganciclotriphosphate appears to function both as an invii-, 45,‘45,2’5this method of administration is being hibitor of, and as a faulty substrate for, CMV studied (see section III C). DNA polymerase with host cellular polymerase In animal studies ganciclovir is teratogenic being much less sensitive.278,438 Ganciclovir triand carcinogenic, and causes azoospermia (Synphosphate is incorporated into CMV DNA with a tex Research, Investigator’s Monograph, 1987). reduction of DNA chain elongation. This effect is The most frequent adverse effects clinically have reversible and virus production resumes when been hematologic, primarily neutropenia and ganciclovir is removed from the media.267.42”The thrombocytopenia. These occur in about 40% drug is therefore virustatic. The initial phosand 20% of patients, respectively. However, sephorylating reaction producing ganciclovir vere dose limiting neutropenia (5OO/pL) and monophosphate is rate-limiting for the synthesis thrombocytopenia (25,OOO/pL) occur in about of ganciclovir triphosphate. CMV does not pro20% and 10%.46 These are usually reversible with

of high-dose acyclovir has also been used successfully in some patients.’ l’s’44A study in England of isolates of HSV 1 obtained from 40 primary ocular infections in immunocompetent patients found 7.5% to have reduced sensitivity and 2.5% to be resistant to acyclovir.56 On the other hand, a second English study found no resistance of HSV type 1 viruses, although one HSV type 2 isolate was resistant in vitro to all antivirals tested.*s’ Acyclovir-resistant VZV has caused hyperkeratotic skin lesions in HIV infected patients after longterm oral acyclovir suppressive therapy.“’ 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.365

30

Surv Ophthalmol 37 (1) July-August 1992

TEICH ET AL

discontinuation of ganciclovir, but irreversible neutropenia has been reported.46 Neutropenia is more common in patients with AIDS, but thrombocytopenia is more common with immunodeliciencies other than AIDS.45 Other less commonly reported associated adverse effects include fever, rash, phlebitis (like acyclovir, ganciclovir has a pH of ll), nausea, hepatocellular dysfunction, and central nervous system symptoms (e.g., confUsion).46*9s.ssrSymptoms of neurotoxicity may occur in the presence of renal impairment, and are reversible with proper dosage adjustmentg3 Although case reports suggest that the effect of ganciclovir in immunocompromised children is similar to that in adults,‘g*‘0s~‘28*‘77additional studies are required to determine its efficacy, safety and optimal dosage both in immunocompromised children and in congenital cytomegalovirus inclusion disease in infants. Ganciclovir is not approved for pediatric use. B.

SYSTEMIC USES

Because of its toxicity, the use of ganciclovir has been limited to AIDS and other immunosuppressed patients with life- or sight-threatening CMV infections. Clinical improvement has been found in 65% or more of patients in uncontrolled studies of nonocular CMV syndromes in AIDS patients, particularly patients with CMV esophagitis, colitis, wasting syndrome, and possibly pneumonia.4”~55~2’g~24’~255 However, statistically significant clinical efficacy has not been established by randomized trials. Variable responses have been described in central nervous system disease.‘3g~255 Prophylactic ganciclovir treatment improves the survival of bone-marrow transplant recipients who are excreting CMV.s7sa In bone-marrow transplant recipients with CMV pneumonia, virologic responses without a reduction in mortality have been observed with ganciclovir treatment alone’s8 or in combination with corticosteroids.347 The combined use of ganciclovir and anti-CMV immune globulin in these patients has been associated with a better survival rate than that in historical controls.“8,347*378Uncontrolled studies have also suggested that renal or hearttransplant recipients and other immunosuppressed patients with CMV pneumonia or other CMV syndromes may have a good response to ganciclovir treatment.‘24~‘84~230 Patients with AIDS and CMV syndromes may have a relapse of their disease when ganciclovir is discontinued.46*55r’24*222,255 The benefits of maintaining these patients with nonocular disease on

Fig. 3. Top: CMV retinitis superior to left optic disc in an AIDS patient. Center: Healing of this area of retinitis 3 weeks following a S-week induction course of ganciclovir. The patient did not receive maintenance ganciclovir treatment. Bottom: One week later there is an obvious recurrence of retinitis at the temporal edge of the atrophic scar.

SYSTEMIC

ANTMRAL

DRUGS

USED

IN OPHTHALMOLOGY

TABLE 3 Gancicloair

Creatinine Clearance* (mliminlkc1 >l.l 0.7-1.0 0.4-0.6 SO.3

hours

Induction

Maintenance

5.0 2.5 2.5 1.25

5.0 2.5 1.25 0.625

Dosing interval (hours) Induction 12 12 24 24

(140 - age) *Creatinine clearante for men = (72)(serum creatinine

Maintenance 24 24 24 24

[mgidl])

Creatinine clearance for women = 0.85x male value

low-dose ganciclovir for acute recurrences, determined. C. OPHTHALMIC

or 5 mg/kg

12 hourly

for 1O-2 1 days.4”*74,

1"4,1XX.200,?07.222.256,274.310.:114.358 There

Dosage with Renal Impairment

Ganciclovir dose (mgjkg)

31

versus reinduction therapy have not been adequately

USES

Ganciclovir is the first drug with FDA-approved labeling for the treatment of CMV retinitis in immunocompromised individuals. Despite the disadvantages of intravenous administration and potential bone marrow toxicity, it represents a major advance in the treatment of what had been an almost uniformly progressive disorder leading to blindness within weeks to months in AIDS patients.‘yX,“‘3,524.3g’ CMV retinitis occurs only in immunosuppressed persons.“4’ Most studies have estimated a 20% prevalence of CMV retinitis in AIDS patients.I09'152.198'2"7"22'"'9,991 In 2% of AIDS patients, CMV retinitis is the first manifestation of disease.9g4 The currently recommended dosage is 5 mg/kg every 12 hours for 14-2 1 days of initial or induction treatment. This is followed by a permanent maintenance dosage of 5 mglkg once daily every day or 6 mg/kg once daily for five out of seven days. The dosage, however, must be reduced in the presence of renal dysfunction (Table 3). 1. Induction Therapy Early reports yielded encouraging shortterm results for intravenous ganciclovir treatment of CMV retinitis.“.‘“” Subsequently, 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 eight

has

been

no

evidence for a difference in either efficacy or toxicity of either of the two induction dosage regimens.46 Although these studies appear to indicate a beneficial effect of ganciclovir, they were not randomized or controlled and did not have standardized, objective criteria for assessing disease outcome. More recently, Holland et al”’ in a controlled retrospective study used a strict standardized system of assessing retinal photographs to determine that an induction course of ganciclovir stops or delays the progression of CMV retinitis. Disease progressed in 94% of untreated patients, but only 43% of treated patients. The proportion of treated patients with progression in this study is higher than in previous studies because the strict photographic criteria allowed detection of small degrees of lesion enlargement and because enlarged lesions were considered to have progressed even if there were signs of decreased activity of the retinitis by the end of the study. Visual acuity is not a generally useful parameter in assessing the response to treatment, since it will not improve unless there is a decrease in any coexisting macular edema or vitritis. The final vision depends mainly on the initial anatomic location of the infection. In one study of ganciclovir, 61% of eyes had a final visual acuity of 201200 or worse,2oo while in another, only 18% had vision this poor and almost 75% could ultimately see 20/40 or better.17” Retinitis resolution usually begins within one to two weeks. Regression is reflected in a decreased opacification of lesion margins, lack of further enlargement of lesions, and resolution of However, there is any vasculitis. 18X.I97,2OO,2O8,:4lO,~il4 occasionally some enlargement of the lesions in the first week, even with successful therapy.‘gg,998 Complete healing usually requires three or four weeks. 197207.310 Ganciclovir reduces and delays but does not eliminate the possibility of involvement of the second eye in unilaterally affected patients. Jabs et alzo7 found that among 15 untreated patients with unilateral CMV retinitis, 9 (60%) developed contralateral disease while none of 18 treated patients developed lesions in the second eye. Gross et al”” in a larger study of longterm maintenance ganciclovir reported that only 15% developed contralateral retinitis. 2. Maintenance Therapy The virostatic

action

of ganciclovir

on CMV is

32

Surv Ophthalmol

37 (1) July-August

1992

TEICH ET AL

TABLE 4 Studies of Longtem Maintenance Ganciclovir

Author

Number of Patients Bilateral

Retinal Detach-

Time to

rence

Recurrence

52%

42%

16%

76%

55%

18

63%

50%

6 weeks (treated 5 days per week) 8 weeks (treated 7 days per week) 3-17 weeks

24%

38%

-

23

52%

30%

4-6 months

22%

13%

48%

14

-

50%

8 weeks

-

31%

-80%

22

35%

27%

7 weeks

14%

29%

-90%

Orellana 1987

33

Holland 1987 Henderly 1987 Jacobson 1988 Jabs 1989 Gross 1989

Recur-

Leukopenia (varying defini-

58

42%

36%

21 weeks

manifested clinically by the recurrence of CMV retinitis (usually at the margins of preexisting healed lesions) following successful induction therapy in almost all AIDS patients within 2-6 weeks of its discontinuation (Fig. 3).‘2,46,74*‘36. ‘8*~200~274~3’4*s58 Histopathologic, electron microscopic, and immunofluorescent studies of eyes treated with ganciclovir have demonstrated the persistence of viral particles in the retina.g’,325,42’ Ganciclovir, via reversible inhibition of CMV DNApolymerase, appears to function by limiting viral DNA synthesis and the subsequent packaging of viral DNA into infectious units, but does not eliminate all viruses nor prevent viral protein With the removal of gancisynthesis. g1~267*s25~40’~423 clovir, DNA synthesis resumes and infectious virus reap1 ears.267,423 Most stuaies of maintenance ganciclovir therapy of CMV retinitis have utilized a dosage of 5 mg/kg once daily for 5-7 days a week. Lower or less frequent doses have been generally ineffective.“~46~‘36*274~358~447 Although available evidence indicates that ganciclovir is beneficial in delaying the recurrence of CMV retinitis, there have been no 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 (25-35 mglkg per week) maintenance therapy compared to 47 days in those receiving low dose (IO-15 mg/kg

ment

19%

tions)

-

Mortality

39%

Mean Survival Time (months) 5

6 5.4 (median) (10 ifrzs;ond to Ganciclovir) 8 (median)

per week) or no maintenance.46 In a small randomized study, Jacobson et al found the median time to retinitis progression following 10 days of ganciclovir induction to be increased from 16 to 42 days by maintenance ganciclovir therapy.‘“’ Data from the six largest studies of longterm maintenance ganciclovir therapy of CMV retinitis are presented in Table 4. Unfortunately, the definitions of recurrence in these studies are not uniform and are often subjective. Recurrence or reactivation occurs in 27-50% of patients despite the use of maintenance ganciclovir and is most commonly noted after 2-4 months.‘73~‘sg~200~207~ 222~3’o Jacobson has pointed out that with once daily 5 mg/kg ganciclovir, serum levels are below the ED,, for CMV for about half the day.“*’ Recurrences may possibly be related to the patient’s underlying immune status.‘73.207 Possibly, if these patients were to survive long enough in the face of continued deterioration in their immune function, they might all ultimately develop recurrent retinitis. One might, therefore, expect studies with longer follow-up to have higher recurrence rates. About one-third of recurrences may take the subtle pattern of a “smoldering” retinitis,““,“’ which can sometimes be detected only by comparing serial fundus photographs. Recurrences are most commonly due to inadequate serum levels of ganciclovir for a particular patient’s immune status rather than ganciclovir

33

SYSTEMIC ANTIVIRAL DRUGS USED IN OPHTHALMOLOGY resistance, as is indicated by the good response of most recurrences to reinduction therapy.‘73’88, L’BO*s”’ However, ganciclovir-resistant strains of CMV have been reported”0.‘2Y in 7.6% of CMV retinitis patients treated for three months or more. It is postulated that cells infected with resistant CMV strains may fail to phosphorylate ganciclovir. ’ ‘O Ganciclovir resistance could become more frequent as its usage increases. Retinal detachments occur despite successful longterm maintenance ganciclovir treatment .of CMV retinitis in roughly 15-20% of patients (Table 5). Although retinal detachments can predate the initiation of ganciclovir therapy,‘07,“57 the healed necrotic areas may be more susceptible to their development.I5”,““,‘XX,‘O7.422 The major toxicity of ganciclovir in studies of maintenance ganciclovir therapy of CMV retinitis has been myelosuppression resulting in neutropenia, or less commonly, thrombocytoIt has been suggested that dosepenia. ‘xx~‘07~3”’ limiting neutropenia (which occurs in up to may be related to peak serum levels of 29%)2”’ the drug, and some cases of neutropenia may be stabilized by administering the maintenance dosage in two divided doses daily.“’ 3. Effects

of Survival

An important consideration is whether ganciclovir treatment of CMV retinitis can affect survival in AIDS patients, as there are usually simultaneous tissue-invasive CMV infections in other organs as well.“‘” In 1984 the median survival after the diagnosis of CMV retinitis in AIDS patients not treated with ganciclovir was only 120 days.“” In comparison, more recent studies of maintenance therapy with ganciclovir demonstrate median survival times of 5-8 months (Table 5). However, it is uncertain as to what degree this improved survival can be attributed to ganciclovir treatment as opposed to prior therapy with zidovudine, improved treatment and prophylaxis of other opportunistic infections, or earlier diagnosis of CMV retinitis. Kotler et aly4’ in a small, nonrandomized, retrospective study of AIDS patients with disseminated CMV infection found ganciclovir therapy to prolong survival from 63 to 162 days. Jacobson et a1,224 on the other hand, did not demonstrate a survival advantage of ganciclovir-treated patients with retinitis compared to untreated AIDS patients without retinitis. Ganciclovir treatment can promote body cell mass repletion in AIDS patients with serious CMV infections,‘4’ which is partly attributed to an improved sense of well-being with

improved appetite.‘8n,24’,3’o In retinitis patients, this might reflect an effect of ganciclovir on early occult CMV infections elsewhere in the bodY.‘“s.3’0 It has also been theorized that ganciclovir could improve survival by limiting a possible transactivating effect of CMV on HIV.9gX Holland et a1,20’ in a large, non-randomized, retrospective study, found that patients treated with ganciclovir had a statistically significant longer survival after the diagnosis of CMV retinitis (median, seven months) than untreated patients (median, two months). This suggests (but does not prove) that ganciclovir does improve survival. 4. Concurrent

Use of Zidovudine

Zidovudine, the only drug which has been shown to prolong survival in AIDS patients,‘“’ must usually be discontinued when ganciclovir therapy is begun. This is due to the synergistic bone marrow toxicity of this combination, especially in causing neutropenia. Up to 90% of patients on longterm ganciclovir therapy for CMV retinitis must discontinue zidovudine therapy.“” Cases of prolonged pancytopenia have occurred with this combination.2’6 Hochster et al”” have shown that full dose (1,200 mg/day) zidovudine given with ganciclovir is rarely tolerated. At a reduced zidovudine dosage of 600 mglday, over 80% of patients suffer severe to life-threatening hematologic toxicity with this combination. However, about one-third of patients could tolerate a zidovudine dosage of 300 mglday, and, overall, only three out of 40 patients had to leave this study due to hematologic toxicity. A reasonable approach may be to discontinue zidovudine during ganciclovir induction, but to initiate or resume its use at a reduced dosage of 100 mg every eight hours during ganciclovir maintenance treatment. 52 The clinical effectiveness of this dosage, however, has not been proven. Close hematologic monitoring is mandatory. 5. Alternative

Strategies

A method for treating or preventing the myelotoxicity of ganciclovir is to coadminister recombinant granulocyte-macrophage colonystimulating factor (GM-CSF) or granulocyte colony stimulating factor (G-CSF) with ganciclovir. GM-CSF and G-CSF are hematologic growth factors that can stimulate the bone marrow production of leukocytes. Subcutaneous GM-CSF used daily in conjunction with intravenous ganciclovir can prevent or reverse dose-limiting

1992

TEICH ET AL

neutropenia and allow successful longterm treatment of CMV retinitis in AIDS and bone marrow transplant patients.‘4X,‘75,‘81 It may also allow simultaneous use of ganciclovir and zidovudine.‘“’ However, GM-CSF may worsen thrombocytopenis,“’ and has the potential for growth of neoplastic cells. 36’ G-CSF can cause bone pain.30’ In summary, preliminary findings are encouraging and the results of prospective trials of combined ganciclovir with GM-CSF or G-CSF are awaited. In patients who are unwilling or unable to undergo intravenous therapy in the face of progressive vision-threatening retinitis, intravitreal use of ganciclovir might be considered. This modality is not an FDA-labeled use of the drug. Henry et al showed that an intravitreal dosage of 200 Kg in 0.1 ml sterile water gives intravitreal ganciclovir levels above the ED,, of CMV for 62 hours with a half-life of 13.3 hours.‘g’ Induction theoretically requires twice weekly injections for two to three weeks. This dosage appears to be nontoxic to the retina, although available data is limited, and toxicity may be difficult to detect in these diseased eyes.48~88~‘82~‘86~‘*7~‘~~‘~424 One patient who was inadvertently given multiple injections of 10 times this dosage did not exhibit “obvious” retinal toxicity.“’ Single 400 pg injections and 300 kg/ml in vitrectomy infusion solutions have been tolerated by rabbit eyes.‘8’*383 Repeated weekly injections in rabbit eyes have demonstrated electroretinographic and electron-micrographic (but not clinical) evidence of retinal toxicity.47’ Although only small numbers have been studied, 78-100% of patients have responded to twice weekly 200 p.g or 400 PLginjections of intravitreal ganciclovir.48~65~88~‘87~42g The higher dose is not more effective, but could be more toxic.65 Maintenance treatment is given as a once weekly injection. Recurrences are at least as likely as with intravenous treatment.4”~65~8x~‘82~‘87~42g Bacterial endophthalmitis,4”“8z*‘86~‘87 retinal detachments 65,‘87*42g and vitreous hemorrhage4’s’j5 are poteniially serious complications of this therapy. Although intravitreal ganciclovir avoids systemic toxicity, it also has no effect on CMV viremia or infections elsewhere in the body, and it does not protect the other eye from CMV infection.65 Its greatest potential use may be as an interim treatment in patients unable to initiate or continue the use of intravenous ganciclovir or foscarnet. Theoretically, longterm release of the drug from an intraocular sustained-release device or from intravitreal liposomes might allow a decreased Further studies are frequency of injections. 32g*36g needed.

An effective oral form of ganciclovir for maintenance therapy would be desirable. The bioavailability of oral ganciclovir ranges from 3-9%. 45,‘45.2’5Both oral ganciclovir solution 200 mg/kg every six hours and 1000 mg capsules given every eight hours result in mean plasma C max higher than the ID,,‘s for many isolates of CMV.‘45,2’5,332 Furthermore, plasma levels were higher six hours after a single 1000 mg oral dose than a 200 mg intravenous dose, although the C max was much lower with the oral dose.45 Therefore, oral ganciclovir may possibly have a role in longterm maintenance therapy of CMV retinitis. Preliminary findings ofthe manufacturer indicate that the median time to recurrence of retinitis in patients receiving oral ganciclovir following two months of therapy with intravenous

34

Surv Ophthalmol

37 (1) July-August

ganciclovir is about 70 days (Buhles WC: personal communication). Further studies of the e&acy and toxicity of oral ganciclovir are in progress. 6. Therapeutic

Dilemmas

Ganciclovir is clearly indicated in the treatment of rapidly progressive or vision-threatening retinitis adjacent to the macula or optic nerve in immunocompromised adults. It is less obvious whether treatment should be initiated for small peripheral lesions. In the absence of active CMV disease elsewhere in the body it may be reasonable to withhold treatment until there is significant progression of CMV retinitis, thereby delaying the need for a longterm indwelling central venous line with its attendant risk of sepsis.344a A similar dilemma occurs in the case of a patient who is blind in one eye due to CMV retinitis, but without involvement in the second eye. One approach is to continue maintenance therapy to reduce the chance of involvement of the second eye. It may be equally justifiable to simply observe the patient at frequent intervals and initiate treatment at the first sign of involvement. If possible, the patient should take an active part in these decisions. Studies of the Ocular Complications of AIDS (SOCA) in collaboration with the AIDS Clinical Trials Group has performed a multicenter randomized controlled study of CMV retinitis (The Foscarnet-Ganciclovir CMV Retinitis Trial) funded by the National Eye Institute (Table 5). Recently published data indicate that the two drugs are equally effective for treating CMV retinitis, but that there is a survival benefit to AIDS patients using foscarnet except in those with decreased renal function, who benefit from ganciclovir.4’3” This is described further in the

SYSTEMIC ANTMRAL foscarnet

35

DRUGS USED IN OPHTHALMOLOGY TABLE

section.

Grading of Retinitis in SOCA CMV Retinitis Trial

IV. Foscarnet Foscarnet (phosphonoformic acid; PFA) was recently approved by the FDA to treat CMV retinitis in AIDS patients, for which use it is about as effective as ganciclovir.4’3”~3’2 It differs from acyciovir, ganciclovir, zidovudine and vidarabine in that it is not a nucleoside analogue, but, rather, is a pyrophosphate analogue. Although clinical experience with this drug is limited, it appears also to be useful in the treatment of CMV infections in immunocompromised patients who are unresponsive to, or intolerant of, ganciclovir’23. 129.‘92,22I,256,~92.43O.444

and

in

the

treatment

of

acy_

clovir-resistant herpetic infections.57,‘25,2’2@‘,365,472 Foscarnet offers an advantage over ganciclovir in that it does not lower the neutrophil count and, therefore, can be used concomitantly with zidovudine. Unfortunately, like ganciclovir, it must be administered intravenously. A. MECHANISM OF ACTION, COLOGY, AND TOXICITY

5

Zone 1: Extends 2 optic disc diameters (3000 microns) from the center of the macula and 1 optic disc diameter (1500 microns) from the edge of the optic disc. Zone 2: Area between Zone 1 and Zone 3. Zone 3: Area anterior to the ampullae of the vortex veins. All eyes in Zone 1 or with greater than 25% of Zone 2 and Zone 3 involvement receive immediate randomized treatment with ganciclovir or foscarnet induction for 2 weeks followed by once daily maintenance. Eyes with less than 25% Zone 2 and Zone 3 involvement are randomized to immediate treatment or deferred treatment if patient agrees. Zidovudine permitted in deferred or foscarnet treatment groups. Zidovudine not permitted during ganciclovir induction but low dose allowed during ganciclovir maintenance.

PHARMA-

Foscarnet is a pyrophosphate analogue of phosphonoacetic acid (Fig. 1) with in vitro activity against all known human herpes viruses (including CMV, EBV, and HSV type-6), hepatitis B virus (HBV), and some retroviruses, including HIV.2”.‘6’,2’4*907.“7’Its antiviral activity is exerted via a selective reversible and noncompetitive in- I hibition of viral specific DNA polymerases and reverse transcriptases (RNA polymerases) at concentrations that do not affect cellular DNA polymerases.237 Since foscarnet directly affects the pyrophosphate binding site of DNA polymerase, it does not require phosphorylation to an active form.‘07 It has, therefore, potential utility in the treatment of thymidine kinase deficient acyclovir-resistant HSV and VZV infections57,lYZ.:j64.Y65,47:! and ganciclovir-resistant CMV infections.‘29,‘9’*2’7 A further advantage over ganciclovir is foscarnet’s intrinsic anti-HIV effect~“14,“5X*“71.4”0 This could make foscarnet a desirable alternative for the treatment of CMV infections in AIDS. Most strains of CMV are inhibited by 100-300 uM of foscarnet,‘“’ 98% of HIV replication is inhibited by 132 ILM,“” and the IDso for acyclovir resistant HSV has been 100 p,M or less.“” Foscarnet is not metabolized in the body and is rapidly eliminated in the urine via renal tubular secretion and glomerular filtration.>” Therefore, the dosage must be adjusted in patients with impaired renal function. Plasma concentrations during and after intravenous in-

fusion are described by a three-compartment model. The disposition of foscarnet is triphasic with mean half-lives of 0.45,3.3, and 18 hoursgg5 Foscarnet sequesters in bone with a very long terminal half-life that can be months.“07~“g6 In AIDS patients, up to 20% of intravenously administered drug may be deposited in bone seven days after infusion. 3g6 In HIV-infected patients foscarnet penetrates into the cerebrospinal fluid in concentrations varying from 13% to 68% of the plasma concentration.sg6 Foscarnet is administered intravenously. Early studies had used a dosing regimen of a bolus of 20 mg/kg over 30 minutes, followed by a continuous infusion of 230 mg/kg/24 hours for 2-3 weeks. A preferable regimen is 60 mg/kg over one to two hours three times daily. In HIV-infected patients the plasma half-life of foscarnet after a two-hour intravenous dosage of 60 mg/kg is about four hours, with virtually no drug detectable after 23 hours.‘” This yields peak plasma levels above the ID,, for most CMV strains lOs221.307.352 Oral absorption of foscarnet is very poor with ineffective serum drug levels and frequent gastrointestinal side-effects.3g5 When 4000 mg of foscarnet was given orally in a water solution every six hours for three days, peak plasma concentrations were nondetectable in four of six patients. Calculated detectable oral bioavailability varied from 12% to 22%. Similar to ganciclovir, foscarnet is adminis-

36

SW-V Ophthalmol 37 (1) July-August 1992

TEICH ET AL

Fig. 4. Ltft: Progressive CMV retinitis in an AIDS patient despite 3 weeks of induction therapy with ganciclovir. Right: Healing of retinitis in the same patient 6 weeks following the institution of foscarnet.

tered in a biphasic manner. There is an initial week induction period with an intermittent infusion of 60 mg/kg over one to two hours given every eight hours. This is followed by a maintenance regimen of 90-120 mg/kg once daily given over two hours indefinitely. Azotemia is the most common serious adverse effect. The incidence of renal impairment has been reported to be as high as 45% in AIDS patients. 1zs~221~258~450 However, the intermittent, rather than constant, intravenous infusion method of induction reduces the incidence of nephrotoxicity to about 25%.2”~312~430In almost all patients with adequate follow-up, the elevations in serum creatinine have been reversible (usually within 24 weeks) following dosage reduction or cessation of medication. Since foscarnet is renally excreted and nephrotoxic, constant monitoring of renal function with dosage adjustment based on the creatinine clearance is critical (Table 6). Hydration with normal saline or 5% dextrose solution intravenously may decrease the incidence of renal toxicity, especially during maintenance therapy.‘04 Foscarnet has been used successfully in a hemodialysis-dependent patient with careful monitoring of peak plasma levels.“64 Foscarnet administration has been associated with changes in serum calcium, phosphorus, and magnesium exceeding 10% of baseline. In various studies involving AIDS patients, elevations in serum calcium have been reported in 27-79% of those treated, whereas decreases have been observed in 7-43%.‘“~2’3~25*~“07*3g5~430 The most probable mechanism for acute hypocalcemia is 2-3

thought to involve chelation of the drug with ionized calcium.g 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.473 The effects of foscarnet on serum calcium and phosphorus (and secondarily on parathyroid hormone levels) are due additionally to sequestration of the drug in bone, but there may also be a role for the nephrotoxic effect of foscarnet in inhibiting renal phosphate secretion.3g5p474 Anemia is the most common hematologic effect of foscarnet with a decrease in hemoglobin concentration occurring in 20-50% of AIDS patients.‘2g*‘32~‘6’*22’~444 Other adverse effects include: elevated hepatic enzymess5*; hallucinations, tremors and seizures2’3~352~3g5*430; nausea, vomiting, diarrhea and abdominal pain22”g5s 430,444; headaches393; local irritation at the infusion site’3Z,3g5*444;nephrogenic diabetes insipidus’30; and genital and oral erosions.‘62,436 B. SYSTEMIC USES Foscarnet has been used successfully, and is superior to vidarabine, in the treatment of acyclovir-resistant herpes simplex virus infections 125,273,364,366.472 which have occurred predominantly in patients with AIDS. Foscarnet also may be effective in the treatment of acyclovirresistant herpes zoster infections in AIDS patients.2’2*3”5The dosage used in treating HSV and VZV (40 mg/kg eight hourly) is lower than in CMV infections. Foscarnet has been used to treat serious CMV

37

SYSTEMIC ANTIVIRAL DRUGS USED IN OPHTHALMOLOGY infections in bone marrow and renal transplant About two-thirds of the patients recipients. 7*237,352 in these uncontrolled trials have shown some improvement clinically and virologically, but not in mortality. The initial clinical responses to foscarnet appear to be similar to those observed with ganciclovir. Foscarnet has also been demonstrated to have an anti-HIV effect, as measured by the serum p24 antigen of HIV, but whether this is of clinical significance has not been determined 26,132~16'~2'4~312 C. OPHTHALMIC

USES

1. Induction Therapy Foscarnet appears to be about as effective as ganciclovir for the initial 2-3-week induction therapy of CMV retinitis in immunocompromised (predominantly AIDS) patients.‘2g,22’,258*3’2, 3g2,430*444 Approximately 90% of such patients have had anatomic improvement or stabilization of CMV retinal lesions. The induction dosage is usually administered as an intermittent infusion of 60 mg/kg every eight hours. Foscarnet does not cause neutropenia, thereby allowing full dose zidovudine therapy to continue, and it may even have an inherent anti-HIV effect.‘2g~2’4~24’~ 25*~3’2~37’~430 Foscarnet therapy also has been effective in treating ganciclovir-resistant CMV retinitisl23,2'7 (Fig. 4) and may be a reasonable alternative in acyclovir-resistant herpes zoster ophthalmicus in AIDS patients.2’2s365 However, clinical experience with this drug is more limited than that with ganciclovir. As with ganciclovir, it generally requires over one week to detect a clinical response to treatment,258 but occasionally regression is noted within a few days.444 2. Maintenance Therapy As with ganciclovir, chronic maintenance therapy with foscarnet is required to treat CMV retinitis in AIDS patients. 22’,258The optimal maintenance dosage is not known, but 90-120 mg/kg once daily has been the most effective.2’3’3’2 Adequate intravenous hydration is especially critical during maintenance therapy.‘04*3’2 Initial studies suggested that foscarnet maintenance was less effective than ganciclovir in preventing recurrent retinitis, but those studies used lower maintenance dosages of one-third the induction dose or 60 mg/kg once on each of five days a week.‘2g,22’,258 Recently, Palestine et a1312 performed a prospective randomized controlled trial of foscarnet in the treatment of CMV retinitis in AIDS. Foscarnet was administered in an

TABLE 6 Foscarnet Dosage

Creatinine clearance* (mVmin/kg)

Foscarnet dose

Induction

Every 8 hours

21.6 1.5 1.4 1.3 1.2 1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4

60.0 56.5 53.0 49.4 45.9 42.4 38.9 35.3 31.8 28.3 24.8 21.2 17.7

Maintenance

Everv 24 Hours

21.4 1.2-1.4 1.0-1.2 0.8-I .O 0.6-0.8 0.4-0.6 *Creatinine

hv&d

90 78 75 71 63 57

120 104 100 94 84 76

clear- = (140-age)

ante for men

(72)(serum

creatinine

[mg/dl])

Creatinine clearance for women = 0.85x male value Discontinue

use if serum creatinine

~2.9 mg/dl.

induction dosage of 60 mg/kg eight-hourly for three weeks, followed by a maintenance regimen of 90 mg/kg once each day. By strict photographic criteria, the mean time to progression of retinitis was increased from about three weeks in controls to 13 weeks in those treated with foscarnet. This clearly demonstrates a beneficial effect of the drug and is comparable to results reported with ganciclovir. There is preliminary evidence that a dosage of 120 mg/kg daily may further delay retinitis progression without an increase in nephrotoxicity or anemia.2’3 However, there may be an increase in serious neurotoxicity including seizures with this higher dosage that is possibly related to serum ionized hypocalcemia 213,2'9.:i12 Foscarnet therapy prolongs life in AIDS patients more than ganciclovir does, possibly because of its anti-HIV effect and because it can be used in conjunction with zidovudine.224*3’2,413a However, foscarnet usage requires, due to its

38

Surv Ophthalmol 37 (1) July-August 1992

TEICH ET AL

metabolic and nephrotoxic effects, closer monitoring and more frequent dosage adjustment than does ganciclovir.

0

NH2

3. SOCA Study41SP The SOCA Foscarnet-Ganciclovir CMV Retinitis Trial (Table 6) was recently suspended because of a survival benefit in the group assigned to initial foscarnet therapy (34% mortality versus 51% in those assigned to ganciclovir). The two drugs were equally effective in treating CMV retinitis in AIDS patients, but there was a fourmonth median survival advantage to initial treatment with foscarnet (12 months) compared to ganciclovir (8 months). This difference could not be fully explained by the increased zidovudine usage in the foscarnet group and it could not be determined why patients treated with foscarnet lived longer. A subgroup of patients who entered the study with mildly decreased renal function (predicted creatinine clearance less than 1.2 ml/mm/kg), however, had a longer survival with ganciclovir. These findings suggest that foscarnet may be the preferable initial treatment for CMV retinitis in AIDS, except possibly for patients with decreased renal lirnction.4’3a It is not known, however, if the concomitant usage of myeloproliferative growth factors (G-CSF, CMCSF) or didanosine (DDI) with ganciclovir might alter these results. These findings should be tempered by the fact that foscarnet was less well tolerated than ganciclovir. More patients switched from foscarnet to ganciclovir due to toxicity than vice versa (20% versus 2%). Finally, there is in vitro evidence for additive or synergistic effects of the combination of foscarnet and ganciclovir on CMV.‘“*‘@’ Perhaps in the future it will be desirable to use the two drugs together at low doses to reduce their toxicity or in tandem to prevent the development of resistance.302a

V. Drugs of Limited Usefulness to Ophthalmologists A. ZIDOWDINE 1. Mechanism of Action, Pharmacology, and Toxicity Zidovudine (azidothymidine, AZT,3’-azido-3’deoxythymidine) is the first drug to be approved by the FDA for the treatment of AIDS. It is a dideoxynucleoside analog of thymidine in which the S’hydroxyl is replaced by an azido group (Fig. 5). In common with other nucleoside analogs, it must be converted to its triphosphate form in order to exert an antiretroviral effect.14’

F

0

.

G

0

H

Fig. 5. Chemical structures of new antiretroviral agents. 3-azido-3-deoxythymidine (AZT) or zidovudine (E), 2,3,-dideoxy-cytidine (ddC) (F), 2,3-dideoxyinosine (dd1) (G), and 2,3_dideoxythymidine or D4T (W

Zidovudine triphosphate inhibits the reverse transcriptase of HIV- 1,2N*367 and, thereby, prevents the production of DNA chains from which further retroviral RNA and proteins can be transcribed. Zidovudine triphosphate may also act as a DNA chain terminator.2g5 Zidovudine is well absorbed from the gastrointestinal tract. It is rapidly converted into an inactive metabolite via hepatic glucuronidation. Zidovudine does enter the cerebrospinal fluid, but its intraocular penetration is uncertain.‘4’.465 Severe anemia and neutropenia are the usual dose-limiting toxicities.35’ The synergistic hematologic toxicities of zidovudine and ganciclovir have been discussed. Longterm zidovudine therapy has infrequently been associated with a toxic myopathy.” Zidovudine has also been reported to cause hypertrichosis of the eyelashes.*” Although acetominophen has been suspected of increasing zidovudine toxicity, a pharmacokinetic interaction has not been demonstrated.40g Zidovudine can cause cell transformation in vitro and is carcinogenic in rodents.”

SYSTEMIC 2. Systemic

ANTIVIRAL

DRUGS USED IN OPHTHALMOLOGY

Uses

Zidovudine has contributed to an increase in median survival in AIDS from less than nine months to more than two years.“’ Orally administered, it prolongs life and increases CD4 lymphocyte counts in patients with AIDS or AIDSrelated complex,‘4” and it delays the progression to AIDS in asymptomatic patients with HIV infection and CD4 lymphocyte counts of less than 500 cells/mm.J “‘4.43gA lower dose of 100 mg every four hours (500 mg daily) is just as effective and better tolerated than twice this dose used in has also been of early studies.4”g Zidovudine benefit in HIV-associated neurologic disease:i79.469 at the higher dose. ‘36 At least six weeks of therapy is needed for the beneficial effects of zidovudine to become apparent.14’ Its chronic use in early HIV disease must be weighed against its toxicity and the development of resistance.““j 3. Ophthalmic

Uses

HIV has been found in the retina of patients both with and without coexisting CMV infections 47.J:ifi.391.99X,3991 t might allow increased expression causing

of CMV via direct enhancement”gg or by dysfunction of ocular immune mechanisms.45,""6 Zidovudine, in theory, could indirectly benefit CMV retinitis in AIDS patients by inhibiting these effects despite its lack of in vitro activity against CMV.“’ Unfortunately, zidovudine is rarely effective in the treatment of CMV retinitis.‘“’ There have, however, been two case reports describing the regression of CMV retinitis in AIDS patients associated with the use of zidovudine 200 mg every four hours.g0.‘7H The retinitis regressed two months after an initial progression. Although unproven, it may be reasonable to attempt zidovudine treatment alone in selected AIDS patients with non vision-threatening retinitis who have no evidence of systemic CMV infection. There has been speculation that zidovudine therapy might initially worsen CMV retinitis via its myelosuppressive effects, which may precede a partial restoration of cell-mediated immunity.“’ Circumstantial evidence for a beneficial effect of antiretroviral treatment on CMV retinitis was described in three patients who were using zidovudine and/or ribavirin plus acyclovir.“” All had retinal lesions typical of healed or healing CMV retinitis. These patients may have had an improved immune status as a result of using antiretroviral drugs, although a possible effect of acyclovir cannot be entirely discounted. Farrel et al’“’ described an HIV-seropositive

39

man with chronic iridocyclitis and anterior vitritis in whom HIV was isolated from the aqueous humor. The uveitis was virtually resolved within a month following the initiation of oral zidovudine therapy. The authors believe this represented a direct antiretroviral effect of the drug. Further experience is necessary to corroborate this effect. It does seem reasonable to attempt zidovudine treatment of uveitis in an HIV-infected patient if other infectious causes of intraocular inflammation are not present, as HIV has been found in the iris.“7 Caution is warranted in view of a report of reversible zidovudine-associated cystoid macular edema, which occurred in a patient with chronic bilateral iritis who had previously had a presumptive diagnosis of and treatment for syphilis.24g 4. Post-Exposure

HIV Prophylaxis

Zidovudine is of potential value to ophthalmologic surgeons for post-exposure prophylaxis in health care workers who have suffered sticks with needles contaminated with blood from HIV-infected patients. The small but real risk of acquiring an HIV infection and the lack of adequate data from which to predict the efficacy and toxicity of zidovudine prophylaxis complicate this decision. The risk for HIV transmission following a single percutaneous exposure is estimated to be 0.3%,18’ but it may be higher for deep cuts or exposure to large volumes ofblood. No infections have been reported following mucous membrane exposure.‘Hg In animal studies, zidovudine given immediately after exposure retards the course of retroviral infections, but the relevance of these studies to human HIV infection is not known.““,‘“’ It has been suggested that zidovudine be administered within four hours of exposure and preferably within 30 minutes.‘“’ At the National Institutes of Health, employees reporting percutaneous or mucous membrane exposure within 24 hours are offered zidovudine 200 mg every four hours for six weeks.“” Others recommend treatment for massive exposures (e.g., injections or transfusions of HIV-containing blood), endorse it for deep needlesticks, and do not encourage it but make it available for less severe exposures. “’ There are reported cases of failure of postexposure zidovudine prophylaxis. ?JS.2’?4 B. RELATED

DIDEOXYNUCLEOTIDES

The dideoxynucleotides didanosine (DDI) and dideoxycytidine (DDC) are potent inhibitors of HIV replication. They are chemically related

40

Surv Ophthalmol

37 (1) July-August

1992

to zidovudine (Fig. 5) and similarly must be converted to the triphosphate form for activity and are orally administered.*“” These drugs may prove to be useful for HIV-related ophthalmic conditions, but clinical data are limited. They are minimally toxic to bone marrow and may be used with ganciclovir. 2g7,466The FDA recently approved DDI to treat patients with advanced AIDS who are intolerant of, or unresponsive to, zidovudine treatment. The major toxic effects are painful peripheral neuropathy and acute Hyperuricemia, rash, and inpancreatitis. 250v468 creased levels of hepatic transaminases can also occur.358a One case of optic neuritis associated with DDI use has been reported.246 A dose-related peripheral atrophy of the retinal pigment epithelium has been noted in 7% of children (but no adults) using DDI.44” DDC has demonstrated some benefit in uiuo, but the development of a painful peripheral neuropathy has limited its use.285,467Recent data suggests that lower doses or alternating the drug with zidovudine could be effective and possibly less toxic.400 C. INTERFERONS 1. Mechanism

of Action and Toxicity

Interferons are proteins that exert a nonspecific antiviral activity in cells by inducing the synthesis of RNA and protein.‘” In addition, they have antiproliferative and immunomodulatory effects. Natural interferons are produced by the stimulation of certain types of cells by viral and other inducers, whereas recombinant DNA-derived preparations are produced by the expression of genes that have been inserted into foreign cell systems. The three major classes of interferons are designated interferon-alpha (leukocyte interferon-beta (fibroblast interinterferon), feron), and interferon-gamma (immune interferon), which were originally distinguished by the cell type producing them.2”~78 Recombinant techniques have produced all three interferons in large quantities, which have made their clinical usage practical. Most commonly, interferons are administered intramuscularly or subcutaneously. They have frequent adverse effects and almost always cause an influenza-like syndrome.““~25’834’ Subcutaneously administered interferon-alpha has been associated with hypertrichosis of the eyelashes.27.‘46 Topical interferon has had few ocular adverse effects,282~402but can cause an allergic reaction.Y55 Intravitreal interferon has been nontoxic to rabbit eyes.4Y7

TEICH ET AL 2. Systemic

Uses

Used systemically, interferons have been beneficial in the treatment of hepatitis Bg5,y26 and hepatitis C virus infectionsg4*‘06; AIDS-associated Kaposi’s sarcoma’72~242~244~2g2; early HIV infections25’; genital (condyloma acuminata) and laryngeal papillomas caused by the human papillomavirus’“g~‘ss~34g~445; and, chronic granulomatous disease.16’ Although of some benefit in genital HSV245 and VZV infections,8*2848460interferons are less effective and more toxic than acyclovir. There is evidence for a CMV-suppressive effect of prophylactic alpha interferon in renal transplant recipients,lg3 but not in HIV-positive patients.172.25’ 3. Ophthalmic

Uses

There is currently no FDA-labeled ophthalmic indication for the use of interferons. When used topically for investigational use, interferon appears to be of some benefit in treating HSV dendritic keratitis,225~282~4’6~44s including acyclovir-resistant HSV-keratitis in AIDS,282 and has a potentiating effect with acyclovir or trifluridine.72~gg~100~308~420 There is quite limited preliminary evidence for a possible benefit of topical interferon in adenoviral keratoconjunctivitiszo6s 354*355 and in decreasing the spread of enteroviral acute hemorrhagic conjunctivitis.408 It is doubtful that the frequent toxic effects of interferons would allow their systemic use for such selflimited infections. Systemic alpha interferon is ineffective in the treatment or prevention of CMV retinitis in AIDS.60~‘72*244~25’ Despite an in vitro synergistic ancoadtiviral effect on CMV, 344 beta-interferon ministered with a reduced ganciclovir maintenance dose in AIDS patients did not prevent retinitis recurrence.‘15 Systemic interferon alpha treatment of recurrent conjunctival papillomas in conjunction with surgical excision has been attempted.‘57 Two of five patients remained tumor free, but three had recurrences upon tapering or discontinuing interferon therapy. Interferon therapy seemed to be tumor-suppressive, but not curative, in these human papilloma virus-related lesions. In the absence of controls, it is difficult to interpret these results. D. IMMUNOGLOBULINS Intravenous immunoglobulin preparations may be useful in the treatment or prophylaxis of certain viral diseases, especially in patients with

SYSTEMIC

ANTMRAL

41

DRUGS USED IN OPHTHALMOLOGY

deficiencies. The mode of action is UC but most likely involves antiviral antibodies in the preparation. It is also possible that infused antibodies prevent immune-mediated cell damage by blocking the recognition of infected cells by cytotoxic T-lympyocytes.‘* Intravenous immunoglobulins are of potential value in CMV infections. Prophylactic immunoglobulins in transplant recipients may reduce immune

::

known,

the risk of developing CMV pneumonia.‘x~7g~2g0~ 4D5.4”.462 However, intravenous immunoglobulins alone have little efficacy in the treatment of CMV infections, including CMV retinitis.2H.22” Combining anti-CMV immunoglobulin with ganciclovir has given favorable results in bone-marrow transplant recipients with CMV pneumonia,“‘, “46.97xbut does not improve efficacy in the treatment of CMV retinitis in AIDS.‘“” There is some interest in the potential use of intravenous immunoglobulins containing monoclonal antibodies against CMV404 for the treatment of CMV retinitis in AIDS patients as an adjunct to ganciclovir (Jabs D: personal communication). Intravenous immunoglobulins have also been reported to be of some efficacy in the treatment of Kawasaki’s disease”*” and echovirus-associated meningoencephalitis and polymyositis in patients with hypogammaglobulinemia.X”

E. NEWER

EXPERIMENTAL

AGENTS

The increasing number of cases of CMV retinitis in HIV-infected patients has revitalized interest in the antiviral properties of pyrimidine nucleoside analogs such as FIAC (Z’fluoro-5iodo-aracytosine), FMAU, and FIAU (Fig. 6). FIAC and FIAU (its primary deaminated uracil metabolite) are active in vitro against HSV-1 and 2, VZV, and CMV.fi7,‘4”.‘“g In a study of VZV infections in immunocompromised patients, FIAC was superior to vidarabine.2”0 However, AIDS patients who were treated with FIAC have developed neurotoxicity and sudden rapid disseminated CMV infections.‘“” It is not apparent whether any clinical role for FIAC exists. Hopefully, other analogs such as FIAU will prove to be more effective and less toxic. Levamisole is an antihelminthic agent which improves the function of cells involved in cellmediated immunity.4’g Clinical experience with levamisole is quite limited and there are no double-blind studies that prove its efficacy in viral infections. A favorable response of herpetic stroma1 keratitis in rabbits has been reported,40J but an uncontrolled clinica trial of oral levamisole

I

Fig. 6. Chemical structures of new experimental CMV agents. 1- f2’deoxy -2’~Buoro-1 -B-D-arabinofuranosyl)-54odocytosine(FIAC) (I), I-(2’deoxy-Y-fluoro-lB-D-arabinofuranosyl)-5-iodouracil (FIAU) (J).

for this condition found it to be of dubious value.““” Ampligen is a specific form of mismatched doubIe-stranded RNA which retains its lymphokine-inducing effect, but is less toxic. There is conflicting data as to whether ampligen might be of benefit in HIV-infected patients.503’g5 There is some in vitro evidence that ampligen has activity against CMV, but there is no clinical evidence of effectiveness.

VI. Conclusion The identification of viral enzymes and proteins that serve as molecular targets for drugs has ushered in a new era in the development of systemic antiviral agents. This has occurred at a time of increased numbers of herpes virus infections as well as an epidemic of HIV-l infections. Most of the agents discussed herein have been designed to combat these viruses. It is incumbent upon the ophthalmologist to have some familiarity with these agents in view of the increasing occurrence of ocular viral infections which are now treatable. This is especially relevant to the treatment of herpes zoster ophthalmicus, the acute retinal necrosis syndrome, and CMV retinitis occurring in AIDS patients. The ophthalmologist is in a unique position to diagnose the infection, monitor the response to treatment, and detect recurrences of disease. Knowledge of the effects and toxicities of the agents described in this review may allow the ophthalmologist to more rationally assist in decisions pertaining to the initiation or discontinuation of therapy. Unfortunately, these agents have not been a

1992

TEICH ET AL

panacea. Resistant viral strains have appeared,lg’ currently available antiviral drugs are unable to eradicate the latent state of herpes viruses and HIV, and drugs such as ganciclovir and foscarnet require longterm intravenous administration. It is hoped that with advances in the technologies of molecular biology and gene-cloning the development of new antivirals which are safe, easily administered, and more effective against a wider variety of viruses will be forthcoming.

rics. Am J Dis Child 143:1307-1316, 1989 20. Balfour HH Jr, Bean B, Mitchell CD, et al: Acyclovir in immunocompromised patients with cytomegalovirus disease. Am J Med 73 (suppl 14):243-248, 1982 21. Balfour HH Jr: Intravenous acyclovir therapy for varicella in immunocompromised children. J Pediatr 104: 134-136, 1984 22. Balfour HH Jr, Kelly JM, Suarez CS, et al: Acyclovir treatment of varicella in otherwise healthy children. J Pediatr 116:633-639, 1990 23. Baron S, Tyring SK, Fleischmann WR Jr, et al: The interferons: mechanisms of action and clinical applications. JAMA 266~1375-1383, 1991 24. Bean B, Braun C, Balfour HH Jr: Acyclovir therapy for acute herpes zoster. Lancet 11:118-121, 1982 25. Bean B, Aeppli D: Adverse effects of high-dose intravenous acyclovir in ambulatory patients with acute herpes zoster. J Infect Dis 151:362-365, 1985 26. Bergdahl S, Sonnerborg A, Larrson A, et al: Declining levels of HIV p24 antigen in serum during treatment with foscarnet. Lancet 1:1052, 1988 27. Berglund EF, Burton GV, Mills GM, Nichols GM: Hypertrichosis of the eyelashes associated with interferonalpha therapy for chronic granulocytic leukemia. South Med J 83:363, 1990 28. Berkman SA, Lee ML, Gale RP: Clinical uses of intravenous immunoglobulins. Ann Intern Med 112:278-292, 29. Beyer CF, Arens MQ, Hill GA, et al: Oral acyclovir reduces the incidence of recurrent herpes simplex keratitis in rabbits after penetrating keratoplasty. Arch Ophthalmol 107:1200-1205, 1989 30. Beyer CF, Hill JM, Kaufman HE: Antivirals and interferons. Ophthalmol Clin 2:51-63, 1989 31. Bialasiewicz AA, Jahn GJ: Systemische Acyclovir Therapie bei Rezidivierender durch Herpes Simplex Virus bedingter Keratouveitis. Klin Monatsbl Augenheilkd 185: 539-542, 1984 32. Biron KK, Elion GB: In vitro susceptibility of varicellazoster virus to acyclovir. Antimicrob AgentsChemother 18:443-447, 1980 33. Bloom JN, Palestine AG: The diagnosis of cytomegalovirus retinitis. Ann Intern Med 109:963-969, 1988 34. Blumenkranz MS, Culbertson WW, Clarkson JG, et al: Treatment of the acute retinal necrosis syndrome with intravenous acyclovir. Ophthalmology 933296-300, 1986 35. Borden EC, Hawkins MJ, Sielaff KM, et al: Clinical and biological effects of recombinant interferon-beta administered intravenously daily in phase I trial. J Znterferon Res 8:357-366, 1988 36. Bridgen D, Rosling AE, Woods NC: Renal function after acyclovir intravenous injection. Am J Med 73 (suppl IA):l82-185, 1982 37. Browning DJ, Blumenkranz MS, Culbertson WW, et al: Association of varicella zoster dermatitis with acute retinal necrosis syndrome. Ophthalmology 94:602-606, 1987 38. Bryson YJ, Dillon M, Lovett M, et al: Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir: A randomized double-blind controlled trial in normal subjects. N Engl J Med 308:916-921, 1983 39. Buchanan RA, Kinkel AW, Alford CA, et al: Plasma levels and urinary excretion of vidarabine after repeated dosing. Clin Pharmacol Ther 27:690-696, 1980 40. Buchanan RA, Hess F: Vidarabine (Vira A) pharmacoly;;rrd clinical experience. Pharmacol Ther 8: 143-l 7 1,

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Outline I. Vidarabine of action, pharmacology, and toxicity B. Systemic uses C. Ophthalmic uses I I. Acyclovir of action, pharmacology, and A. Mechanism toxicity B. Systemic uses C. Ophthalmic uses 1. Herpes simplex virus 2. Herpes zoster ophthalmicus 3. Acute retinal necrosis syndrome 4. Epstein-Barr virus 5. Cytomegalovirus D. Resistance III. Ganciclovir of action, pharmacology, and A. Mechanism toxicity B. Systemic uses C. Ophthalmic uses 1. Induction therapy 2. Maintenance therapy 3. Effects on survival 4. Concurrent use of zidovudine 5. Alternative strategies 6. Therapeutic dilemmas IV. Foscarnet of action, pharmacology, and A. Mechanism toxicity B. Systemic uses C. Ophthalmic uses 1. Induction therapy 2. Maintenance therapy 3. SOCA study V. Drugs of limited usefulness to ophthalmologists A. Zidovudine 1. Mechanism of action, pharmacology, and toxicity 2. Systemic uses 3. Ophthalmic uses 4. Post-exposure HIV prophylaxis Related dideoxynucleotides B. lnterferons C. 1. Mechanism of action, pharmacology, and toxicity 2. Systemic uses 3. Ophthalmic uses Immunoglobulins D. Newer experimental agents E. A.

Mechanism

Reprint address: Alan H. Friedman, M.D., Dept. of Ophthalmology, Mt. Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029. This work was supported in part by an unrestricted grant from Research to Prevent Blindness, New York, NY.