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Drugs

, Volume 37, Issue 3, pp 233–309 | Cite as

Acyclovir

An Updated Review of its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Efficacy
  • John J. O’Brien
  • Deborah M. Campoli-Richards
Drug Evaluation

Summary

Synopsis

Acyclovir (aciclovir) is a nucleoside antiviral drug with antiviral activity in vitro against members of the herpes group of DNA viruses. As an established treatment of herpes simplex infection, intravenous, oral and to a lesser extent topical formulations of acyclovir provide significant therapeutic benefit in genital herpes simplex and recurrent orofacial herpes simplex. The effect of acyclovir therapy is maximised by early initiation of treatment, especially in non-primary infection which tends to have a less protracted course than the primary episode. Long term prophylactic oral acyclovir, in patients with frequent episodes of genital herpes simplex, totally suppresses recurrences in the majority of subjects; as with other infections responding to acyclovir, viral latency is not eradicated and pretreatment frequencies of recurrence return after discontinuation of treatment. Caution should accompany the prophylactic use of acyclovir in the general population, due to the theoretical risk of the emergence of viral strains resistant to acyclovir and other agents whose mechanism of action is dependent on viral thymidine kinase. Intravenous acyclovir is the treatment of choice in biopsy-proven herpes simplex encephalitis in adults, and has also been successful in the treatment of disseminated herpes simplex in pregnancy and herpes neonatorium. Intravenous and oral acyclovir protect against dissemination and progression of varicella zoster virus infection, but do not protect against post-herpetic neuralgia. In immunocompromised patients, intravenous, oral and topical acyclovir shorten the clinical course of herpes simplex infections while prophylaxis with oral or intravenous dosage forms suppresses reactivation of infection during the period of drug administration. Ophthalmic application of 3% acyclovir ointment rapidly heals herpetic dendritic corneal ulcers and superficial herpetic keratitis.

Thus, despite an inability to eradicate latent virus, acyclovir administered in therapeutic or prophylactic fashion is now the standard antiviral therapy in several manifestations of herpes simplex virus infection, and indeed represents a major advance in this regard. With the exception of varicella zoster virus infections, early optimism concerning the use of the drug in diseases due to other herpes viruses has generally not been supported in clinical investigations.

Antiviral Activity

Acyclovir exhibits in vitro activity against herpes simplex virus types 1 and 2, varicella zoster virus, Epstein-Barr virus and, to a lesser degree, cytomegalovirus. Although quantitative results vary considerably depending on the viral strain and methodological aspects of the assay system employed, in general herpes simplex virus type 1 is the most susceptible, followed in descending order of susceptibility by herpes simplex type 2, varicella zoster virus, Epstein-Barr virus and cytomegalovirus. Against herpes simplex virus types 1 and 2, acyclovir is generally more potent in vitro than the nucleoside analogues idoxuridine, trifluridine or vidarabine, of comparable potency to 2′-fluoro-5-iodoarabi-nosylcytosine (FIAC) and ganciclovir [DHPG;9-(1,3-dihydroxy-2-propoxymethyl) guanine], and more (herpes simplex type 2) or less (herpes simplex type 1) potent than bromovinyldeoxyuridine. The relative potencies of acyclovir and other antivirals against varicella zoster virus have varied between studies, but the drug is less active in vitro against cytomegalovirus than idoxuridine, trifluridine, vidarabine and ganciclovir. Acyclovir appears able to inhibit the productive cycle, but not the latent phase, of Epstein-Barr virus. Depending on the drug concentrations and cell lines involved, combinations of acyclovir plus one of the other nucleoside antivirals or one of the variously derived interferons have generally exhibited additive to synergistic activity against certain herpesviruses, including cytomegalovirus. Replication of herpes simplex virus in explant ganglionic or tissue cultures is readily interrupted during incubation with acyclovir; reversion to latency is noted after several days’ exposure to the drug. Acyclovir appears to eradicate part of the latent viral reservoir, as assessed by the reactivation rate after drug removal. Alternate exposure of explant ganglionic cultures to acyclovir-containing and drug-free media has been associated with statistically significant reductions in the proportion of reactivable virus, dependent on the frequency and duration of alternating applications.

The mechanism of action of acyclovir involves highly selective inhibition of herpes virus DNA replication, via enhanced uptake in herpes virus-infected cells and phos-phorylation by viral thymidine kinase, and the substrate specificity of acyclovir triphosphate for viral, rather than cellular, DNA polymerase. Epstein-Barr virus and especially cytomegalovirus which does not encode for a thymidine kinase, have reduced susceptibility to acyclovir; the mechanism of action of acyclovir against these viruses may differ from that which operates in herpes simplex.

The antiviral efficacy of acyclovir administered by various routes has been demonstrated in in vivo animal models of ocular, cutaneous, genital, CNS and neonatal infections due to herpes simplex viruses. In addition to being influenced by factors such as the animal species, size of viral inoculum, drug dosage, and route and frequency of administration employed, the efficacy of acyclovir treatment correlated closely with the rapidity of its initiation following viral inoculation. Indeed, initiation of topical or systemic acyclovir within 24 hours of viral challenge has been found to prevent the establishment of viral latency following primary infection, and reductions in the number of reactivable latent herpes simplex foci following acyclovir treatment have been observed in some in vivo studies, but acyclovir therapy has not resulted in eradication of established, latent virus from neuronal ganglia. When compared with other antiviral agents in in vivo models of herpes simplex virus infections, acyclovir was generally at least as effective as other nucleoside analogues, although research tools such as the newer 2′-fluoropyrimidines and 5′-vinylpyrimidines offered greater protection than acyclovir in certain models, when the agents were administered on an equimolar basis.

Acyclovir-resistant strains of herpes simplex virus and varicella zoster virus arise chiefly from mutations in the genes affecting the production of viral thymidine kinase, and are readily produced in vitro. Such strains exhibit variable cross-resistance to other antivirals, depending on the specific mutation(s) conferring resistance and the mechanism of action of the alternative drug. Clinically, acyclovir-resistant strains have been reported very infrequently overall, and usually in association with chronic mucocutaneous lesions in severely immunocompromised patients receiving extended courses of acyclovir. The reduced in vivo pathogenicity and ability to establish latency of the vast majority of clinically isolated resistant strains indicates that they are unlikely to cause refractory or aggressive infection in immunocompetent individuals; this supposition has been supported by clinical studies to date. In addition, comparisons of the in vitro acyclovir susceptibility of viral isolates from patients receiving chronic oral suppressive acyclovir for several months have not revealed statistically significant reductions in viral susceptibility following treatment; when recurrences did ‘break through’, they almost always resolved upon administration of therapeutic or increased dosage of acyclovir. However, a recent study reported a correlation between the in vitro susceptibility of pretreatment herpes simplex virus isolates and the occurrence of mucocutaneous lesions during prophylactic acyclovir administration. Continued monitoring is required to further define the occurrence and clinical significance of viral resistance to acyclovir.

Pharmacokinetic Studies

Repeated 8-hourly intravenous doses of 2.5 to 15.0 mg/kg provide clinically useful steady-state mean plasma acyclovir concentrations, ranging from 6.7 to 20.6 mg/L, respectively. The bioavailability of oral acyclovir is limited at 15 to 30%. Increasing the contact time of orally administered acyclovir with the absorptive area of the gut, by administering the dose as a direct duodenal infusion over 4 hours, produced a marked increase in bioavailability, indicating that absorption may be capacity-limited, especially at higher dosages. Delivery of topical acyclovir to deeper tissues may be markedly influenced by the formulation vehicle; systemic absorption with topical administration has not been detected. Substantial intraocular penetration is evidenced by a mean acyclovir concentration of 1.7 mg/L in aqueous humour with multidose application of the 3% ointment every 5 hours, and peak concentrations of 6.7 and 5.2 mg/L, respectively, in the aqueous and vitreous humour following a single 25mg subconjunctival injection.

Acyclovir was detected at autopsy in the kidney, lung, nervous tissue, liver and heart of a patient who had received high-dose intravenous therapy with the drug. Cerebrospinal fluid and skin vesicle concentrations following intravenous therapy, and saliva and tear fluid concentrations following oral therapy, were approximately 50%, 100%, 13% and 18% of simultaneous plasma concentrations, respectively. Acyclovir crosses the placenta and accumulates in breast milk such that the milk concentration in a lactating woman was more than 3 times the simultaneous plasma acyclovir concentration. In vivo protein binding of acyclovir is low (9 to 24%) and independent of the plasma drug concentration.

Renal excretion is the major route of elimination of acyclovir in subjects with normal renal capacity. Depending on the creatinine clearance, up to 80% of a dose is excreted unchanged in the urine, while the remainder is metabolised to inactive derivatives. The elimination half-life in adults with normal renal function is 2 to 3 hours. As expected, dosage adjustments are required in patients with end-stage renal disease, with the elimination half-life extended in this subgroup to approximately 20 hours, and mean peak plasma concentrations increased approximately 2-fold. Acyclovir is readily haemodialysable, having a dialysis half-life in this situation of about 6 hours. However, continuous ambulatory peritoneal dialysis is much less efficient at removing the drug and the elimination half-life is extended to 14 to 18 hours. Disposition of acyclovir in children is similar to that in adults, but in neonates the relatively underdeveloped renal function results in total body clearance being reduced by two-thirds and the elimination half-life being increased to up to 4 hours.

Therapeutic Trials

Double-blind, placebo-controlled studies in immunocompetent patients have shown intravenous (5 mg/kg 8-hourly), oral (200mg 5 times daily) and, to a lesser extent, topical acyclovir therapy (5% in polyethylene glycol ointment or propylene glycol cream applied 4 to 6 times daily) initiated within 4 days of the first appearance of signs or symptoms to produce significant reductions in the duration of viral shedding and time to complete healing of lesions in initial genital herpes infection. Statistically significant amelioration of the course of infection was most readily demonstrated in the more severe primary initial episode. Pain or dysuria symptoms tended to be less responsive to treatment, especially by topical acyclovir, which was also generally unable to produce statistically significant reductions in new lesion formation. Acyclovir treatment of initial genital herpes did not alter the chronic recurring nature of the infection. However, early, especially patient-initiated, treatment with oral acyclovir at the prodrome of recurrent genital herpes inhibits new lesion formation and viral shedding and reduces episode durations by 1 to 2 days. Nonetheless, due to the shorter duration of recurrent vs initial episodes, the beneficial effects of acyclovir on recurrent episodes are less dramatic. Although results with topical acyclovir in recurrent infection have been somewhat conflicting, the 5% cream has in some placebo-controlled studies exhibited a moderate degree of clinical efficacy, whereas the 5% ointment generally produced only marginal reductions in virological, and little or no amelioration of clinical disease parameters, even with optimal timing of treatment initiation.

Prophylactic oral administration of acyclovir at dosages of 400 to 800 mg/day for 1 to 2 years led to complete suppression of recurrences of genital herpes in approximately 60 to 90% of subjects. Unfortunately recurrence rates returned to pretreatment frequencies after discontinuation of acyclovir. This form of acyclovir therapy was extremely well tolerated and was not associated with the emergence of clinically significant acyclovir resistance.

Acyclovir 5 or 10% ointment has been mostly ineffective for the treatment of recurrent orofacial herpes in immunocompetent patients, although a reduction in healing time of statistical, but limited clinical significance occurred when treatment with the 5% ointment was begun during the prodromal phase. Comparisons of the results obtained in placebo-controlled, double-blind investigations indicate acyclovir 5% cream to be superior to the ointment formulation in treating recurrent orofacial outbreaks, although absolute reductions in symptom duration remain small relative to the duration of a recurrent episode. In contrast, prophylaxis with topical (5% cream) and more especially oral (200mg 4 times daily) acyclovir reduces the severity and frequency of recurrences during treatment in patients with a history of frequent outbreaks.

Acyclovir 3% ophthalmic ointment applied 5 times daily cures 95 to 100% of herpetic dentritic corneal ulcers in approximately 5 days, being at least as effective as idoxuridine 0.5 and 1% ointments, trifluridine formulated as a 2% ointment, and vidarabine 3% ointment, and possibly more rapid in effect than these comparative antivirals. The larger geographic corneal ulcers also respond to acyclovir ophthalmic ointment, a double-masked study revealing no difference in efficacy with that of vidarabine in this indication. Several double-masked comparative studies showed that the combination of acyclovir 3% ophthalmic ointment applied 5 times daily plus once daily application of human α-interferon shortens the time to healing of superficial herpetic keratitis (dendritic or geographic ulcers) by approximately 3 days, from 7 to 9 days for acyclovir plus placebo. Thus, this combination may be a useful advance in the treatment of superficial herpetic keratitis. In contrast, results with the use of systemic (oral) acyclovir 400mg 5 times daily remain equivocal, insufficient duration of therapy being a potentially compromising variable. As might be expected, considering the likely immunological basis of herpetic stromal involvement, acyclovir 3% ophthalmic ointment, applied 5 times daily, is more effective in treating herpetic disciform keratitis (and in a few reported cases, necrotising stromal keratitis) when administered concomitantly with topical corticosteroids. In a double-masked comparison there was no statistically significant difference in the percentage of patients with herpetic disciform keratitis cured, the time to resolution of signs and symptoms, and the time to healing, between patients administered acyclovir or vidarabine ophthalmic ointment 5 times daily, concomitantly with betamethasone 0.1% ophthalmic drops. In herpetic kerato-uveitis, the efficacy of acyclovir 3% ophthalmic ointment applied 5 times daily was not statistically different from that of trifluridine 1% ophthalmic solution applied 6 times daily, although the mean time to healing of corneal ulcers was shorter (p < 0.05) in the trifluridine-treated group; the majority of these patients also received local injection of dexamethasone.

Large collaborative studies comparing intravenous treatment using acyclovir and vidarabine have established acyclovir 10 mg/kg 8-hourly, administered for at least 10 days, to be the treatment of choice for biopsy-proven herpes simplex encephalitis. Acyclovir was found to be particularly beneficial in improving overall survival rates and reducing the incidence of serious sequelae to infection. In case reports, intravenous or oral acyclovir therapy of disseminated herpes simplex of various manifestations in near term pregnancy has been followed by survival, without complications, of mothers and infants. Acyclovir and vidarabine appear to be of comparable efficacy in the treatment of neonatal herpes simplex; antiviral prophylaxis of neonates delivered to mothers with active genital lesions is not generally warranted unless additional risk factors are present.

Further case studies have reported the successful treatment with acyclovir of disseminated herpes simplex accompanied by hepatitis, disseminated primary eczema herpeticum, herpes simplex whitlow and herpes simplex-associated erythema multiforme.

Intravenous acyclovir significantly attenuated the development of rash and pain, and protected against ocular involvement in double-blind placebo-controlled studies in immunocompetent patients with acute herpes zoster. Similar benefit with oral therapy usually required higher dosages (600 to 800mg 5 times daily) than are generally used for herpes simplex infections. Therapeutic efficacy was maximised with early initiation of acyclovir treatment, however the drug did not offer protection against post-herpetic neuralgia and was often associated with recurrence of pain soon after withdrawal. A marked reduction (vs placebo) in the incidence of ocular sequelae associated with trigeminal zoster occurred after 1 year’s follow-up in patients who received acyclovir 600mg 5 times daily for 10 days during an acute episode. In several case reports, acyclovir treatment of herpes zoster-associated encephalitis, varicella pneumonia, and herpes zoster oticus resulted in rapid resolution of infection.

An unconfirmed potential therapeutic benefit of intravenous acyclovir (10 mg/kg 8-hourly) is suggested by a placebo-controlled study in patients with severe infectious mononucleosis. Acyclovir alone or administered sequentially with human lymphoblastoid interferon appears to offer very limited clinical benefit in chronic active hepatitis B infection, although the latter combination administered concurrently is deserving of further investigation in this indication.

Earlier double-blind, placebo-controlled studies in immunocompromised patients with herpes simplex infections have shown intravenous (250 mg/m2 8-hourly) acyclovir therapy to dramatically reduce the period of viral shedding, with parallel improvements occurring in healing parameters. Topical application of the 5% ointment was effective with regard to external lesions, but failed to produce a statistically significant reduction in time to healing. More recently, oral administration of 400mg 5 times daily significantly accelerated the resolution of viral shedding and pain, and reduced time to healing by almost two-thirds, in bone marrow transplant recipients.

Perhaps due to ethical difficulties concerning such studies, there remains a lack of controlled or comparative studies of acyclovir treatment of immunocompromised patients with acute varicella zoster infection. Nevertheless, intravenous dosages of 500 mg/m2 or 10 mg/kg administered 8-hourly in small numbers of patients have been associated in controlled studies with a protective effect against progression and dissemination of infection, although reductions in time to healing did not generally achieve statistical significance. However, in a comparison with vidarabine, intravenous acyclovir was superior in promoting pain relief and cutaneous healing, in addition to providing significantly better protection against dissemination than the alternative antiviral. A further comparative trial failed to confirm an advantage of acyclovir over vidarabine. Topical acyclovir (5% ointment) also favourably influenced the healing of localised herpes zoster when applied within 3 days of the onset of lesions. Recurrence of varicella zoster infection has been regularly reported after completion of acyclovir therapy in immunocompromised subjects.

Despite transient effects on viraemia and possibly viral titre in the target organ, acyclovir treatment of cytomegaloviral pneumonia in immunocompromised patients has resulted in very little clinical improvement, and has not generally improved survival rates. Similarly, a favourable clinical response to acyclovir therapy of Epstein-Barr virus infections does not usually accompany an antiviral effect of the drug in these patients. However, Epstein-Barr virus-associated oral hairy leucoplakia in patients with human immunodeficiency virus infection responded well to high-dose oral acyclovir in case studies.

Immunologically compromised patients have a predictable pattern of reactivation of latent herpes simplex virus. Thus, in a series of placebo-controlled studies in immunocompromised patients, prophylaxis with intravenous or oral acyclovir for periods of up to 6 months produced virtual complete suppression of clinical herpes simplex infection, while virological results were only slightly less impressive. This protection was confined to the period of drug administration, although in some studies in bone marrow recipients an extension of the median time to first reactivation accompanied an increase in the duration of prophylaxis. Varicella zoster virus infection was also suppressed in seropositive patients during prophylaxis, whereas the effect on cytomegalovirus reactivation was less impressive. However, high-dose (500 mg/m2 8-hourly) acyclovir prophylaxis in immunocompromised individuals led to a statistically significant reduction in the occurrence of invasive cytomegaloviral disease and an associated increase in survival in a controlled study. Nonetheless, prophylaxis against late reactivations of varicella and cytomegalovirus with acyclovir is unlikely to be practical.

Adverse Effects

Acyclovir is generally extremely well tolerated. Ophthalmic administration is only rarely associated with spontaneously reported reactions and the association of these with the drug (as opposed to the disease process) is difficult to discern. Topical therapy is only associated with burning or stinging on application, and a mild erythema or drying in a small proportion of patients. The adverse reactions most frequently reported with intravenous acyclovir are inflammation and phlebitis at the injection site. However, 2 important and serious adverse effects associated with intravenous administration are neurological and/or psychiatric effects (lethargy, tremors, confusion, hallucinations, seizures) and renal precipitation of the drug resulting in renal insufficiency. High peak plasma concentrations have been implicated in both of these problems. In addition, the potential for renal complications may be minimised with slow infusion of doses, adequate hydration, and lower dosages in patients with renal dysfunction. Nausea, vomiting, other gastrointestinal symptoms and lightheadedness have also been associated with high peak acyclovir concentrations following intravenous administration. Short term use of oral acyclovir has most commonly been associated with nausea and vomiting. Long term (1 year) use is equally well tolerated, with nausea, vomiting, diarrhoea, stomach pain, rash and headache occurring at an incidence of less than 5% and in a similar percentage of placebo recipients.

Dosage and Administration

Therapy with acyclovir should be initiated as soon as possible following the onset of signs or symptoms.

The recommended dosage of acyclovir 3% ophthalmic ointment is 5 times daily application into the lower conjunctival sac, continued for at least 3 days after complete healing. Topical 5% acyclovir is recommended in non-life-threatening mucocutaneous herpes simplex infection, applied 5 times daily for 5 to 10 days (cream) or 6 times daily for 7 days (ointment).

For the treatment of herpes simplex infections of the skin and mucous membranes, the recommended oral acyclovir dosage is 200mg 5 times daily for 5 days. Lower oral doses of 200mg may prove effective for chronic suppression of recurrent herpes simplex. The optimum dosage for acute treatment of herpes zoster is 800mg 5 times daily by mouth, for 7 days.

An intravenous dosage of 5 mg/kg (adjusted to 250 mg/m2 in children under 12 years) infused over 1 hour every 8 hours for 5 days is recommended for the treatment of herpes simplex and varicella zoster infections in the immunocompetent. For immunocompromised patients with varicella zoster, a higher intravenous dosage of 10 mg/kg (500 mg/ m2 in children under 12 years) should be administered 8-hourly for 7 days. Intravenous administration of acyclovir should be gradual (over 1 hour), with adequate hydration maintained to preclude drug precipitation in the renal tubules. Infusion concentrations should not normally exceed 7 mg/ml.

Dosage reductions are necessary in patients with moderate to severe impairment of renal function, dependent on the degree of impairment.

Keywords

Herpes Simplex Herpes Simplex Type Herpes Zoster Acyclovir Genital Herpes 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© ADIS Press Limited 1989

Authors and Affiliations

  • John J. O’Brien
    • 1
  • Deborah M. Campoli-Richards
    • 1
  1. 1.ADIS Drug Information ServicesAucklandNew Zealand

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