Acyclovir: An overview

INTRODUCTION — Acyclovir is widely used in the treatment of herpesvirus infections, particularly herpes simplex virus (HSV) and varicella-zoster virus (VZV). An overview of the mechanisms of action of and resistance to acyclovir and its major clinical uses will be provided here.

Dosing and treatment of the specific clinical syndromes are described in greater detail on the appropriate topic reviews.

Use of valacyclovir or famciclovir, which are later generation agents with a similar mechanism of action, are discussed elsewhere. (See "Valacyclovir: An overview" and "Famciclovir: An overview".)

MECHANISM OF ACTION — Acyclovir (9-[2-hydroxymethyl]guanine) is a nucleoside analog that selectively inhibits the replication of herpes simplex virus types 1 and 2 (HSV-1, HSV-2) and varicella-zoster virus (VZV). After intracellular uptake, it is converted to acyclovir monophosphate by virally-encoded thymidine kinase. This step does not occur to any significant degree in uninfected cells and thereby lends specificity to the drug's activity. The monophosphate derivative is subsequently converted to acyclovir triphosphate by cellular enzymes.

Acyclovir triphosphate competitively inhibits viral DNA polymerase by acting as an analog to deoxyguanosine triphosphate (dGTP). Incorporation of acyclovir triphosphate into DNA results in chain termination since the absence of a 3' hydroxyl group prevents the attachment of additional nucleosides. Acyclovir triphosphate has a much higher affinity for viral DNA polymerase than for the cellular homolog, yielding a high therapeutic ratio [1,2].

Spectrum of activity — In descending order of susceptibility, acyclovir is active against HSV types 1 and 2 (HSV-1, HSV-2), VZV, and Epstein-Barr virus (EBV) [1]. Cytomegalovirus (CMV), which does not encode thymidine kinase, is resistant at clinically achievable levels. Activity versus human herpes viruses 6 [3] and 8 [4] is similarly limited, and activity versus human herpes virus 7 is not well defined.

Mechanism of resistance — Three mechanisms have been shown to endow herpes simplex viruses with resistance to acyclovir, a phenomenon rare in the immunocompetent host [5,6]:

●Reduced or absent thymidine kinase

●Altered thymidine kinase activity resulting in decreased acyclovir phosphorylation

●Altered viral DNA polymerase with decreased affinity for acyclovir triphosphate

Valacyclovir, which is a prodrug of acyclovir, and famciclovir, which is a prodrug of penciclovir, have a similar mechanism of action as acyclovir. Thus, HSV isolates resistant to acyclovir are also resistant to valacyclovir, famciclovir, and penciclovir.

Resistant herpes simplex viruses have been isolated from a variety of immunocompromised patients, including bone marrow and solid organ transplant recipients and those with the acquired immunodeficiency syndrome (AIDS) [7]. Analysis of isolates from a series of twelve AIDS patients with resistant HSV-2 indicated marked thymidine kinase deficiency in each case; these strains, not surprisingly, were cross-resistant to ganciclovir, which also requires phosphorylation for antiviral activity. However, foscarnet, a pyrophosphate analogue, is also a potent inhibitor of HSV DNA polymerase and does not require phosphorylation for its antiviral activity; in clinical trials, foscarnet has demonstrated efficacy in patients with acyclovir-resistant infections [8,9]. (See "Foscarnet: An overview".)

VZV resistance to acyclovir has been reported in patients with AIDS and other severely immunocompromising conditions. This rare problem usually occurs in the setting of chronic acyclovir therapy and has been linked to mutations in thymidine kinase, resulting in either deficient thymidine kinase or an enzyme with altered substrate specificity [5,10].

BASIC PHARMACOKINETICS — Acyclovir has modest oral bioavailability, about 15 to 30 percent, which decreases with higher doses. As an example, multiple oral doses of 200 to 800 mg yield steady-state peak plasma concentrations of 0.6 to 1.6 mcg/mL, whereas intravenous dosing at 5 to 10 mg/kg every eight hours results in concentrations of 10 to 20 mcg/mL. Thus, the intravenous formulation should be used for serious infections such as disseminated varicella in an immunocompromised host. (See "Treatment of varicella (chickenpox) infection", section on 'Immunocompromised hosts'.)

Acyclovir is not highly bound to plasma protein (about 15 percent) and achieves widespread tissue and fluid penetration, including the cerebrospinal fluid, in which acyclovir concentrations are approximately 50 percent of those in plasma. (See "Herpes simplex virus type 1 encephalitis", section on 'Treatment'.)

Excretion is predominantly renal, both by glomerular filtration and tubular secretion. The plasma half-life is two to three hours in patients with normal renal function; dosage modifications are required in the presence of renal insufficiency, which is a risk factor for acyclovir-related neurotoxicity [11,12].

A buccal tablet formulation of acyclovir, which is placed on the upper gum (rather than swallowed), was approved by the United States Food and Drug Administration (FDA) in 2013 for treatment of recurrent herpes labialis in immunocompetent adults. A single 50 mg tablet yielded a mean salivary concentration of 440 mcg/mL 8 hours after application. However, the plasma concentration of acyclovir that was achieved after administration of the buccal formulation was insufficient to have antiviral activity at nonoral sites [13]. Thus, the buccal tablet should not be used for the treatment of herpes simplex virus (HSV) at nonoral sites.

DOSE ADJUSTMENTS

Reduced renal function — Dose modification of acyclovir is recommended for patients with a reduced estimated glomerular filtration rate (eGFR) [14-16]:

●If administered orally, the dose should be reduced for individuals with an eGFR ≤25 mL/minute/1.73 m²

●If administered intravenously, the dose should be reduced for individuals with an eGFR ≤50 mL/minute/1.73 m²

Detailed dosing recommendations are available in the Acyclovir drug information monograph included within UpToDate.

Obesity — In patients with obesity (eg, BMI ≥30), weight-based dosing should be scaled to ideal body weight (IBW) rather than actual body weight (ABW) to avoid an increased risk of toxicity [15-19]. Acyclovir is hydrophilic, not highly bound to plasma protein, and distributes mainly into body fluids and nonadipose tissue (see 'Basic pharmacokinetics' above). A calculator to determine IBW (using sex, height, and actual body weight) is available separately in UpToDate (calculator 1).

TOXICITY — Acyclovir is remarkably well tolerated in most patients [20]. There are, however, several important types of toxic reactions.

Acute renal failure — Acute renal failure, produced by the precipitation of relatively insoluble acyclovir crystals in the renal tubules, is an occasional complication of intravenous therapy [21,22]. The risk can be minimized by prior hydration (with the urine output maintained above 75 mL/hour) and slow drug infusion over one to two hours [11]. (See "Crystal-induced acute kidney injury".)

Neurologic toxicity — Rare reports of neurologic toxicity have included agitation, tremors, delirium, hallucinations, and myoclonus [23-25]; cases typically occur in patients with underlying renal failure. Severe neurotoxicity, characterized by delirium and coma, has been described at doses as low as 800 mg twice daily in patients requiring dialysis [26]. The potential for this complication is greater in patients treated with peritoneal dialysis, which is associated with minimal removal of acyclovir [27].

USE IN PREGNANCY — Although no controlled studies have been performed to establish the safety of acyclovir during pregnancy, several large observational studies have generated reassuring data:

●In an observational cohort of nearly 838,000 live-born infants in Denmark from 1996 to 2008, 1804 pregnancies had been exposed to acyclovir, valacyclovir, or famciclovir during the first trimester of pregnancy [28]. However, exposure to antiviral therapy was not associated with an increased risk of a congenital anomaly.

●Analysis of 1129 pregnancies exposed to acyclovir, 712 during the first trimester, from 1984 to 1997, failed to reveal an increase in congenital anomalies when compared with the rate expected in the general population [29].

USE OF ACYCLOVIR IN IMMUNOCOMPETENT PATIENTS — Acyclovir is used for the treatment of herpes simplex virus (HSV), herpes zoster, and primary varicella infection in immunocompetent and immunocompromised hosts. It is also occasionally used for post-exposure prophylaxis after exposure to varicella. Further information can be found in the appropriate topic selection.

IF THERE IS AN ACYCLOVIR SHORTAGE — Shortages of intravenous (IV) acyclovir have occurred in the United States [30,31]. IV acyclovir is the drug of choice for: neonates with proven herpes simplex virus (HSV) disease, pregnant women with complicated HSV or varicella-zoster virus (VZV) infection, and individuals with herpes simplex encephalitis. During a shortage, IV acyclovir should be reserved for patients with these infections [31]. However, if IV acyclovir is not available, alternative agents must be used. Clinicians should check the United States Food and Drug Administration (FDA) and the American Society of Health-system pharmacists websites for information about the availability of IV acyclovir.

Overview of alternative agents — Guidance on the management and treatment of these various infections when a shortage occurs is listed below. Consultation with an infectious diseases specialist is recommended. All dosing recommendations for the antiviral agents listed below are for patients with normal renal function; dosage adjustments are required for patients with renal insufficiency.

●Ganciclovir ─ Ganciclovir is an acyclic analog of the nucleoside guanosine that has established antiviral efficacy in the treatment of cytomegalovirus infections. Ganciclovir also inhibits the replication of other herpesviruses in vitro, including HSV-1 and HSV-2; however, there are few clinical data on the use of this antiviral medication for the clinical indications listed above.

Clinicians need to be aware that ganciclovir is associated with more toxicity than acyclovir, particularly bone marrow suppression (anemia, leukopenia and/or thrombocytopenia). Hematologic monitoring is recommended in patients receiving ganciclovir. Ganciclovir should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus. (See "Ganciclovir and valganciclovir: An overview".)

●Foscarnet ─ Foscarnet has been associated with decreased renal function and electrolyte abnormalities. Monitoring of renal function and electrolytes is essential in patients receiving foscarnet. In addition, patients should receive prehydration with normal saline before each dose of foscarnet. The concomitant administration of other nephrotoxic agents should be avoided, when possible. (See "Foscarnet: An overview", section on 'Toxicity'.)

●Cidofovir ─ Cidofovir does not cross the blood-brain barrier and should not be substituted for acyclovir in patients with central nervous system infections.

Management of clinical conditions when IV acyclovir is unavailable

●Herpes simplex encephalitis — For suspected or documented HSV encephalitis we administer ganciclovir (for infants ≤90 days old: 6 mg/kg IV every 12 hours; for infants >90 days old, children, and adults: 5 mg/kg every 12 hours) [31]. If ganciclovir cannot be given, we suggest foscarnet (for infants and children: 60 mg/kg IV every 12 hours; for adults: 90 mg/kg IV every 12 hours or 60 mg/kg IV every 8 hours). (See "Herpes simplex virus type 1 encephalitis", section on 'Treatment'.)

●Neonatal herpes simplex infection — For suspected neonatal HSV infection we suggest ganciclovir (for infants ≤90 days old: 6 mg/kg IV every 12 hours; for infants >90 days old: 5 mg/kg every 12 hours) [31]. If ganciclovir cannot be given, we suggest foscarnet (60 mg/kg IV every 12 hours). The duration of treatment is the same as it would be for acyclovir.

Patients should be monitored closely for response to therapy because there is a lack of clinical experience with ganciclovir for the treatment of neonatal HSV; this includes repeat sampling of cerebrospinal fluid for HSV polymerase chain reaction (PCR). (See "Neonatal herpes simplex virus infection: Management and prevention".)

●Varicella pneumonia — For patients with suspected or documented varicella pneumonia we suggest ganciclovir (for infants <90 days old: 6 mg/kg IV every 12 hours; for infants >90 days old, children, and adults: 5 mg/kg IV every 12 hours) [31]. If ganciclovir cannot be given, we suggest foscarnet (for infants and children: 60 mg/kg IV every 12 hours; for adults: 90 mg/kg IV every 12 hours or 60 mg/kg IV every 8 hours).

●Adults who have improved on IV ganciclovir can be switched to a high dose of oral valacyclovir (in adults: 2000 mg four times daily) provided that they are expected to absorb oral medications adequately. In adults who are not severely ill, it is reasonable to give a lower dose of valacyclovir (1000 mg three times daily). We do not recommend oral acyclovir in this situation since it is not highly bioavailable.

●Disseminated herpes simplex virus infection — HSV infection can cause disseminated disease in immunocompromised and immunocompetent hosts. For infants or for immunocompromised and/or severely ill children and adults, we suggest ganciclovir (for infants <90 days old: 6 mg/kg IV every 12 hours; for infants >90 days old, children, and adults: 5 mg/kg IV every 12 hours) [31]. If ganciclovir cannot be given, we suggest foscarnet (for infants and children: 60 mg/kg IV every 12 hours; for adults: 90 mg/kg IV every 12 hours or 60 mg/kg IV every 8 hours). Adults who are improving on IV therapy can be switched to valacyclovir (1000 mg orally three times daily).

For immunocompetent children or adults who are not severely ill (eg, patients experiencing their initial HSV episode, who may have lesions distant from the site of inoculation), we suggest initial therapy with valacyclovir (for children: 20 mg/kg per dose orally three times daily [maximum dose 1000 mg per dose]; for adults: 1000 mg orally three times daily).

●Disseminated herpes zoster infection — Varicella-zoster virus (VZV) infection can cause disseminated disease in immunocompromised and immunocompetent hosts. For immunocompromised patients or severely ill patients, we suggest ganciclovir (for infants <90 days old: 6 mg/kg IV every 12 hours; for infants >90 days old, children, and adults: 5 mg/kg IV every 12 hours) [31]. If ganciclovir cannot be given, we suggest foscarnet (for infants and children: 60 mg/kg IV every 12 hours; for adults: 90 mg/kg IV every 12 hours or 60 mg/kg IV every 8 hours). Patients who are improving on IV therapy can be switched to valacyclovir (for children: 20 mg/kg per dose orally three times daily [maximum dose 1000 mg per dose]; for adults: 1000 mg orally three times daily).

For immunocompetent patients who are not severely ill, we suggest initial therapy with valacyclovir (for children: 20 mg/kg per dose orally three times daily [maximum dose 1000 mg per dose]; for adults: 1000 mg orally three times daily).

●Esophageal herpes simplex infection — For patients with HSV esophagitis who are unable to take medications orally due to odynophagia, we suggest ganciclovir (5 mg/kg IV every 12 hours). If ganciclovir cannot be given, we suggest foscarnet (40 mg/kg IV every 8 to 12 hours).

●Mucocutaneous herpes simplex infections — Immunocompetent patients with mucocutaneous HSV infection can be treated with oral famciclovir, or valacyclovir, or acyclovir.

SUMMARY AND RECOMMENDATIONS

●Indications – Acyclovir is widely used in the treatment of herpesvirus infections, particularly herpes simplex virus (HSV) and varicella-zoster virus (VZV). (See 'Introduction' above.)

●Mechanism of action – After intracellular uptake, acyclovir is converted to acyclovir monophosphate by virally-encoded thymidine kinase; this step does not occur to any significant degree in uninfected cells and thereby lends specificity to the drug's activity. The monophosphate derivative is subsequently converted to acyclovir triphosphate, which leads to DNA chain termination. (See 'Mechanism of action' above.)

●Risk of resistance – Acyclovir-resistant herpes simplex viruses are uncommon and are typically seen in immunocompromised patients, such as bone marrow and solid organ transplant recipients and those with the AIDS. Acyclovir-resistant herpes viruses are rarely detected in the immunocompetent host. (See 'Mechanism of resistance' above.)

Herpes simplex viral isolates that are resistant to acyclovir are also resistant to valacyclovir, famciclovir, and ganciclovir. Foscarnet can be effective in this clinical scenario.

●Oral versus intravenous therapy – The oral formulation of acyclovir has modest oral bioavailability and is suitable for most patients; however, the intravenous formulation should be used for serious infections (eg, herpes simplex encephalitis, disseminated varicella in an immunocompromised host). (See 'Basic pharmacokinetics' above.)

●Dose adjustments – In patients with reduced kidney function, the dose of acyclovir may need to be reduced depending upon the formulation (intravenous [IV] versus orally [PO]) and the estimated glomerular filtration rate. Detailed dosing recommendations are available in the acyclovir drug information monograph included within UpToDate.

In addition, for patients with a BMI ≥30, weight-based dosing of IV therapy should be scaled to ideal body weight (IBW) rather than actual body weight.

●Toxicity – Acyclovir is generally well tolerated. Rare complications, seen almost exclusively with intravenous therapy, include acute renal failure and neurologic toxicity (eg, agitation, tremors, delirium, hallucinations, and myoclonus). (See 'Toxicity' above.)

●Use in pregnancy – Although no controlled studies among pregnant women have been performed, large observational studies have suggested that acyclovir use during the first trimester of pregnancy is not associated with an increased risk of teratogenicity. (See 'Use in pregnancy' above.)