Aciclovir

Abstract

Aciclovir (acyclovir) is a nucleoside analogue with antiviral activity in vitro against the herpes simplex viruses (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpesvirus 6 (HHV-6). Topical, oral or intravenous aciclovir is well established in the treatment of ophthalmic, mucocutaneous and other HSV infections, with intravenous aciclovir the accepted treatment of choice in herpes simplex encephalitis. The efficacy of aciclovir is increased with early (preferably during the prodromal period) initiation of treatment but, despite significant clinical benefit, viral latency is not eradicated, and pretreatment frequencies of recurrence usually continue after episodic acute treatment is completed. Intravenous administration has also shown benefit in the treatment of severe complications of HSV infection in pregnancy, and neonatal HSV infections. Recurrence of HSV has been completely prevented or significantly reduced during suppressive therapy with oral aciclovir in immunocompetent patients. Use of oral aciclovir is effective but controversial in the treatment of otherwise healthy individuals with varicella (chickenpox), and in some countries it has been recommended for use only in cases which may be potentially severe. The development of rash and pain associated with herpes zoster (shingles) is attenuated with oral or intravenous aciclovir therapy, ocular involvement is prevented, and post-herpetic neuralgia appears to be decreased. Similarly, in a few patients with zoster ophthalmicus, oral aciclovir has reduced the frequency and severity of long term ocular complications and post-herpetic neuralgia, and herpes zoster oticus is improved with intravenous aciclovir. Oral aciclovir has prevented recurrence of HSV genital or orofacial infections during suppressive therapy in > 70% of immunocompetent patients in most clinical trials. Suppression of latent HSV, VZV and CMV infections has been achieved in many immunocompromised patients receiving the oral or intravenous formulations. Aciclovir also appears to offer partial protection from invasive CMV disease in CMV-seropositive bone marrow transplant recipients. The few comparative trials published have shown aciclovir to be at least as effective as other investigated antivirals in the treatment of HSV infections in immunocompetent patients, and more effective than inosine pranobex in the prophylaxis of genital herpes. Similarly, in isolated clinical trials, oral aciclovir appears as effective as topical idoxuridine and oral brivudine in some parameters in immunocompetent patients with VZV infections, and the intravenous formulation appears at least as effective as oral brivudine and intravenous vidarabine in treating these infections in immunocompromised patients. Investigations of a regimen of aciclovir plus zidovudine in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) suggest some advantage for the combination over zidovudine monotherapy in reducing the incidence of opportunistic infections and mortality. However, patient numbers were limited and these preliminary results require substantiation. Aciclovir is well tolerated. Mild gastrointestinal effects may occur with the oral formulation in a few patients, and acute reversible renal failure and neurotoxicity has been associated with high peak plasma aciclovir concentrations, usually in patients receiving intravenous administration. Thus, aciclovir in intravenous, oral and to a lesser extent topical formulations retains its secure position as an effective agent in the therapy and prophylaxis of HSV and VZV infections in immunocompetent and immunocompromised patients, with no clear advantages shown for newer agents over aciclovir in limited comparisons. The role of aciclovir in the prevention of CMV infections in immunocompromised patients is also generally accepted, but its use in diseases caused by other herpes viruses such as EBV and HHV-6 has not been supported in clinical investigations to date. Nonetheless, there appears to be potential for further growth in the role of aciclovir if combination regimens become more accepted in the treatment of viral infections, and if its efficacy in reducing opportunistic infections and associated mortality in patients with AIDS or ARC is confirmed. Aciclovir (acyclovir) selectively inhibits DNA replication of herpes viruses, with low host cell toxicity. The antiviral is preferentially activated in infected cells; initial phosphorylation occurs via viral thymidine kinase, and aciclovir triphosphate (the active derivative obtained from the monophosphate via host cell enzymes) inhibits viral DNA polymerase more readily than the cellular enzyme, thus preventing viral replication. Although Epstein-Barr virus (EBV) appears to have only minimal thymidine kinase activity, EBV DNA polymerase is very susceptible to inhibition by aciclovir triphosphate. Since cytomegalovirus (CMV) does not code for thymidine kinase, and CMV DNA polymerase is poorly inhibited by aciclovir triphosphate formed by cellular enzymes, CMV is less susceptible to aciclovir than are herpes simplex virus (HSV), varicella zoster virus (VZV) and EBV. In descending order of susceptibility, the viruses against which aciclovir exhibits in vitro antiviral activity are HSV-1 and 2, VZV, EBV, human herpesvirus 6 (HHV-6) and CMV. The in vitro activity of aciclovir was generally similar to or greater than that of most other antiviral agents tested against HSV and VZV; ganciclovir, idoxuridine and vidarabine are more potent than aciclovir against CMV; ganciclovir and foscarnet appear to be more potent against HHV-6; and aciclovir appears to have greater activity than penciclovir against EBV. Combination of aciclovir with various antiviral compounds has resulted in synergistic or additive antiviral activity in vitro against HSV, VZV and CMV. Although part of the latent HSV reservoir is eradicated by aciclovir in ganglionic or tissue cultures and replication is readily interrupted, reversion to latency occurs after several days of exposure. The in vivo activity of aciclovir was demonstrated in animal models of HSV ocular, cutaneous, genital, CNS and neonatal infections. Initiation of aciclovir administration within 24 hours of viral challenge can reduce the establishment of viral latency following primary infection, but eradication of established latent virus has not been achieved. Activity as a prophylactic agent has been demonstrated in rabbits with HSV keratitis. Combination with other antiviral agents, such as vidarabine, ribavirin or ribonucleotide reductase inhibitors, has resulted in synergistic effects against HSV infections in animals. Most aciclovir-resistant strains of HSV and VZV have mutations in the thymidine kinase gene which result in little or no production of the enzyme. Resistant HSV strains occur infrequently in immunocompetent patients, and reactivation of these strains from latency is rare. However, aciclovir-resistant HSV strains causing clinical disease are becoming increasingly common among the immunocompromised population. Reports of aciclovir-resistant strains of other herpes viruses are comparatively rare. The pharmacokinetic disposition of intravenous aciclovir is not affected by dose, duration or frequency of administration. Steady-state plasma aciclovir concentrations in immunocompromised patients (6.7 to 20.6 mg/L after intravenous doses of 2.5 to 15.0 mg/kg every 8 hours) are similar to those obtained with equivalent single doses. Absorption of oral aciclovir is slow and variable, with a bioavailability of 15 to 30%. There is no systemic absorption of topical aciclovir from the ointment, but 30 to 50% of the drug reaches the basal epidermis in cutaneous infections treated with the cream formulation, and substantial intraocular penetration occurs with the ophthalmic ointment. Orally or intravenously administered aciclovir is distributed to a wide range of tissues and fluids, crosses the placenta and accumulates in breast milk. Plasma protein binding is 9 to 33%, and is independent of plasma aciclovir concentrations. Drug interactions appear to be scarce. Area under the plasma concentration-time curve values and elimination half-life are increased when aciclovir and probenecid are coadministered. The main metabolite, 9-carboxymethoxymethyl guanine, accounts for about 14% of a dose and is pharmacologically inactive. Since the main route of elimination is via renal excretion, kidney dysfunction affects plasma concentrations, extent of metabolism and rate of elimination of the drug. The elimination half-life in adults with normal renal function is 2 to 3 hours, extending to about 20 hours in patients with end-stage renal failure. The half-life in dialysis patients is 6 to 10 hours, but is prolonged to 13 to 18 hours during continuous ambulatory peritoneal dialysis. In neonates, total body clearance is reduced and elimination half-life is increased to up to 5 hours. In Immunocompetent Patients Double-blind placebo-controlled studies in immunocompetent patients have demonstrated the efficacy of intravenous (5 mg/kg 3 times daily), oral (200mg 5 times daily) and topical (applied 4 to 6 times daily) aciclovir initiated within 4 days of the first symptoms of HSV perigenital infection. The duration of viral shedding and time to complete healing of lesions are significantly reduced, particularly in the primary episode. Topical aciclovir is less effective in ameliorating symptoms than are the other formulations. Comparison of topical aciclovir arid intramuscular interferon-α has demonstrated no significant differences in the treatment of primary genital herpes infection, with a trend in favour of aciclovir in parameters involving time to healing, pain, and viral response. The rate of recurrence of infection is not affected by initial treatment with aciclovir. Most well-controlled trials have shown complete suppression of genital herpes recurrence in 71 to 88% of immunocompetent patients, using prophylaxis with oral aciclovir 800 to 1000 mg/day for up to 2 years. Pretreatment recurrence rates returned on discontinuation of aciclovir. Complete suppression of recurrence for 5 years has been achieved in 20% of patients on aciclovir prophylaxis (800 to 1600 mg/day). Two well-controlled trials have demonstrated a clear advantage for oral aciclovir over oral inosine pranobex in the suppression of recurrent genital HSV infection. Oral aciclovir therapy causes significant improvements in recurrent orofacial and cutaneous infections if begun as early as possible after reactivation. Prophylaxis with topical, and especially oral, aciclovir reduces the severity and frequency of orofacial and cutaneous HSV recurrence during treatment. Reductions in symptoms are small with topical treatment of recurrent orofacial herpes in immunocornpetent patients. Aciclovir 3% ophthalmic ointment 5 times daily eliminates 95 to 100% of herpetic dendritic corneal ulcers in 5 to 9 days, and is at least as effective as idoxuridine 0.5 and 1.0%, trifluridine 2% and vidarabine 3% ointments. The ophthalmic ointment is also as effective as vidarabine in treating geographic corneal ulcers. Combination of aciclovir with topical interferon-α shortens the time to healing of superficial herpetic keratitis by several days compared with aciclovir alone. Oral administration of aciclovir appears to be equivalent or superior to topical administration in the treatment of herpetic disciform keratitis. Addition of topical corticosteroids to the ophthalmic ointment has proved effective in treating herpetic disciform keratitis and necrotising stromal keratitis unresponsive to single agent therapy. Aciclovir ophthalmic ointment is as effective as vidarabine ophthalmic ointment in herpetic disciform keratitis and trifluridine ophthalmic solution in herpetic kerato-uveitis, when corticosteroids are included in the regimens. However, corticosteroids may not be necessary in patients with HSV uveitis previously untreated with corticosteroids if oral aciclovir is added to topical aciclovir therapy. Prophylaxis with oral aciclovir 800 to 1000 mg/day for 12 to 15 months completely prevented HSV keratitis recurrence in all patients undergoing penetrating keratoplasty, compared with a recurrence rate of 44% in an untreated group. The treatment of choice for HSV encephalitis, intravenous aciclovir 10 mg/kg every 8 hours for at least 10 days, improves survival rates and reduces the incidence of serious sequelae to infection. Addition of interferon-β to the regimen provided no advantage in most patients. A placebo-controlled trial of oral aciclovir prophylaxis (800 mg/day for 26 weeks) in HSV erythema multiforme has substantiated previous reports of efficacy. Case studies have reported successful intravenous aciclovir treatment and prophylaxis in patients with HSV meningitis, and successful treatment of HSV-associated encephalitis, disseminated infection and hepatitis in pregnant women, followed by survival of mothers and infants without complications. Intravenous aciclovir and vidarabine appear equally effective in the treatment of neonatal HSV infections including mucocutaneous infection, encephalitis and disseminated disease. There is some controversy over the role of aciclovir in treating varicella (chickenpox) in otherwise healthy individuals, since the disease is usually self-limiting. Nonetheless, oral aciclovir initiated within 24 hours of the appearance of the rash associated with varicella (chickenpox) has resulted in decreased numbers of lesions, duration of new lesion formation, severity or duration of pruritus, time to healing and duration of fever in otherwise healthy children, adolescents and adults in several well-designed studies. Clinical improvement has been noted in a few adults with varicella pneumonia receiving intravenous aciclovir, and maternal mortality rates associated with this complication have been decreased during pregnancy. In patients with herpes zoster (shingles), intravenous (5 mg/kg every 8 hours for at least 5 days) or oral (4000 mg/day for 7 days) aciclovir treatment begun within 72 hours of exanthem onset attenuates the development of rash and pain, offers protection against ocular involvement and appears to decrease the duration of post-herpetic neuralgia. Topical idoxuridine was superior to oral aciclovir in some parameters in one double-blind study, but efficacy was similar in time to disappearance of papulopustules, appearance of first scabs, loss of all scabs, and disappearance of erythema or pain. Oral brivudine was associated with significantly greater reductions in pain and new lesion formation compared with intravenous aciclovir in elderly cancer patients with severe herpes zoster, but there were no differences in time to loss of vesicles or time to full crusting. Although the immediate efficacy of aciclovir ophthalmic ointment in the treatment of zoster ophthalmicus is equivocal, oral aciclovir begun within 72 hours of skin eruption produces significant reductions in the longer term (up to 12 months) in frequency and severity of ocular complications such as dentriform keratopathy, stromal keratitis and anterior uveitis in these patients. Case reports and one small placebo-controlled trial have demonstrated rapid improvement of facial function grade in patients with herpes zoster oticus treated with intravenous aciclovir, and success is also reported in isolated cases of patients with herpes zoster-associated encephalitis, myelitis, idiopathic vocal cord paralysis and Rosai Dorfman disease. Recurrence of severe almost constant aphthae has been prevented or decreased with oral aciclovir 1600 mg/day for 10 weeks. Although trends towards faster improvement have been recorded in 2 double-blind trials of aciclovir versus placebo in patients with infectious mononucleosis, no statistically significant differences were seen. Addition of aciclovir to interferon-α therapy in patients with chronic hepatitis B appears to offer some advantages over monotherapy, but no significant differences in the rate of seroconversion were demonstrated. Aciclovir has prevented postsurgical recurrence of laryngeal papillomatosis in 3 children and improved symptoms of epilepsia partialis continua in 4 patients. In Immunocompromised Patients The efficacy of intravenous (250 mg/m² every 8 hours) or oral (2000 mg/day) aciclovir is well established in the treatment of immunocompromised patients with HSV infections. Severe infections refractory to normal dosages of aciclovir (such as HSV hepatitis, or infections caused by viruses deficient in thymidine kinase activity) may respond to higher dosages, as demonstrated in case reports. Topical administration (5% in polyethylene glycol) reduced the period of viral shedding in renal transplant recipients, but the value of topical aciclovir is limited in severely immunocompromised patients. Viral shedding and/or scabbing time, deterioration in clinical condition and progression of the disease are reduced in immunocompromised patients with VZV infections treated with intravenous aciclovir (500 mg/m² every 8 hours for 5 to 8 days). In this setting aciclovir appears as effective as oral brivudine and at least as effective as intravenous vidarabine. Oral aciclovir is also effective in promoting healing and preventing dissemination of varicella in immunocompromised patients, and topical aciclovir reduced time to pustulation, crusting and healing in immunocompromised patients with localised herpes zoster. Virtually complete suppression of latent HSV or VZV infections during intravenous or oral aciclovir prophylaxis has been demonstrated in most patients at increased risk of recurrence because of bone marrow transplantation, radiotherapy or cytotoxic chemotherapy, while up to 50% of infections which did recur involved asymptomatic viral shedding only. While protection was confined to the period of therapy in most patients, there is evidence that long term prophylaxis may also result in a reduction in the rate of HSV infections, compared to that seen in placebo recipients, after discontinuation of therapy. Oral aciclovir prophylaxis has provided protection against HSV and VZV infections in patients receiving renal transplants, and against HSV infections in liver and heart transplant recipients, with complete suppression of clinical symptoms during treatment in most patients. The incidence of HSV infection was also reduced in renal and heart transplant patients for up to 12 months following withdrawal of aciclovir prophylaxis. High dose oral or continuous infusion of intravenous aciclovir have resulted in resolution of EBV infections such as oral hairy leucoplakia in immunocompromised patients, but reactivation of latent infection occurs frequently on discontinuation of the drug. Similarly, although aciclovir treatment of symptomatic CMV infection in immunocompromised patients has generally resulted in little clinical improvement, continuous infusion has resolved the infection in isolated cases. Aciclovir prophylaxis appears to decrease CMV shedding, and reduce the incidence of clinically evident and invasive CMV disease, and possibly that of associated mortality, in immunocompromised patients with haematological disorders, despite decreased activity compared with prophylaxis against HSV and VZV. The rate of CMV infection after treatment was decreased in some patients. The incidence of CMV infection was reduced by about half (to 36%) during 1 year of observation after a 12-week course of oral aciclovir prophylaxis (800 to 3200 mg/day) in a double-blind trial in renal transplant recipients, and by half to two-thirds (to 18.3 to 30.8%) in...