The immunosuppressive agent mycophenolate mofetil (Chapter 35) potentiates the anti-herpes activity of acyclovir and related agents by depleting intracellular dGTP pools. Acyclovir triphosphate competitively inhibits viral DNA polymerases and, to a much lesser extent, cellular DNA polymerases. Acyclovir triphosphate also is incorporated into viral DNA, where it acts as a chain terminator because of the lack of a 3′-hydroxyl group. By a mechanism termed suicide inactivation, the terminated DNA template containing acyclovir binds the viral DNA polymerase and leads to its irreversible inactivation.
Acyclovir resistance in HSV has been linked to one of three mechanisms: impaired production of viral thymidine kinase, altered thymidine kinase substrate specificity (e.g., phosphorylation of thymidine but not acyclovir), or altered viral DNA polymerase. Alterations in viral enzymes are caused by point mutations and base insertions or deletions in the corresponding genes. Resistant variants are present in native virus populations and in isolates from treated patients. The most common resistance mechanism in clinical HSV isolates is absent or deficient viral thymidine kinase activity; viral DNA polymerase mutants are rare. Phenotypic resistance typically is defined by in vitro inhibitory concentrations of >2-3 μg/mL, which predict failure of therapy in immunocompromised patients.
Acyclovir resistance in VZV isolates is caused by mutations in VZV thymidine kinase and less often by mutations in viral DNA polymerase.
Absorption, Distribution, and Elimination. The oral bioavailability of acyclovir ranges from 10-30% and decreases with increasing dose (Wagstaff et al., 1994). Peak plasma concentrations average 0.4-0.8 μg/mL after 200-mg doses and 1.6 μg/mL after 800-mg doses. Following intravenous dosing, peak and trough plasma concentrations average 9.8 and 0.7 μg/mL after 5 mg/kg every 8 hours and 20.7 and 2.3 μg/mL after 10 mg/kg every 8 hours, respectively.
Valacyclovir is converted rapidly and virtually completely to acyclovir after oral administration in healthy adults. This conversion is thought to result from first-pass intestinal and hepatic metabolism through enzymatic hydrolysis. Unlike acyclovir, valacyclovir is a substrate for intestinal and renal peptide transporters. The relative oral bioavailability of acyclovir increases 3-5 fold to ~70% following valacyclovir administration (Steingrimsdottir et al., 2000). Peak acyclovir concentrations average 5-6 μg/mL following single 1000-mg doses of oral valacyclovir and occur ~2 hours after dosing. Peak plasma concentrations of valacyclovir are only 4% of acyclovir levels. Less than 1% of an administered dose of valacyclovir is recovered in the urine; most is eliminated as acyclovir.
Acyclovir distributes widely in body fluids, including vesicular fluid, aqueous humor, and cerebrospinal fluid (CSF). Compared with plasma, salivary concentrations are low, and vaginal secretion concentrations vary widely. Acyclovir is concentrated in breast milk, amniotic fluid, and placenta. Newborn plasma levels are similar to maternal ones. Percutaneous absorption of acyclovir after topical administration is low.
The mean plasma elimination t1/2 of acyclovir is ~2.5 hours (range: 1.5-6 hours in adults with normal renal function). The elimination t1/2 of acyclovir is ~4 hours in neonates and increases to 20 hours in anuric patients (Wagstaff et al., 1994). Renal excretion of unmetabolized acyclovir by glomerular filtration and tubular secretion is the principal route of elimination. Less than 15% is excreted as 9-carboxymethoxymethylguanine or minor metabolites. The pharmacokinetics of oral acyclovir and valacyclovir appear to be similar in pregnant and nonpregnant women (Kimberlin et al., 1998).
Untoward Effects. Acyclovir generally is well tolerated. Topical acyclovir in a polyethylene glycol base may cause mucosal irritation and transient burning when applied to genital lesions.
Oral acyclovir has been associated infrequently with nausea, diarrhea, rash, or headache and very rarely with renal insufficiency or neurotoxicity. Valacyclovir also may be associated with headache, nausea, diarrhea, nephrotoxicity, and central nervous system (CNS) symptoms. High doses of valacyclovir have been associated with confusion and hallucinations, nephrotoxicity, and uncommonly, severe thrombocytopenic syndromes, sometimes fatal, in immunocompromised patients. Acyclovir has been associated with neutropenia in neonates. Chronic acyclovir suppression of genital herpes has been used safely for up to 10 years. No excess frequency of congenital abnormalities has been recognized in infants born to women exposed to acyclovir during pregnancy (Ratanajamit et al., 2003).
The principal dose-limiting toxicities of intravenous acyclovir are renal insufficiency and CNS side effects. Preexisting renal insufficiency, high doses, and high acyclovir plasma levels (>25 μg/mL) are risk factors for both. Reversible renal dysfunction occurs in ~5% of patients, probably related to high urine levels causing crystalline nephropathy. Manifestations include nausea, emesis, flank pain, and increasing azotemia. Rapid infusion, dehydration, and inadequate urine flow increase the risk. Infusions should be given at a constant rate over at least an hour. Nephrotoxicity usually resolves with drug cessation and volume expansion. Neurotoxicity occurs in 1-4% of patients and may be manifested by altered sensorium, tremor, myoclonus, delirium, seizures, or extrapyramidal signs. Phlebitis following extravasation, rash, diaphoresis, nausea, hypotension, and interstitial nephritis also have been described. Hemodialysis may be useful in severe cases.
Severe somnolence and lethargy may occur with combinations of zidovudine and acyclovir. Concomitant cyclosporine and probably other nephrotoxic agents enhance the risk of nephrotoxicity. Probenecid decreases the acyclovir renal clearance and prolongs the elimination t1/2. Acyclovir may decrease the renal clearance of other drugs eliminated by active renal secretion, such as methotrexate.
Therapeutic Uses. In immunocompetent persons, the clinical benefits of acyclovir and valacyclovir are greater in initial HSV infections than in recurrent ones, which typically are milder in severity. These drugs are particularly useful in immunocompromised patients because these individuals experience both more frequent and more severe HSV and VZV infections. Because VZV is less susceptible than HSV to acyclovir, higher doses must be used for treating varicella-zoster infections than for HSV infections. Oral valacyclovir is as effective as oral acyclovir in HSV infections and more effective for treating herpes zoster.
Herpes Simplex Virus Infections. In initial genital HSV infections, oral acyclovir (200 mg five times daily or 400 mg three times daily for 7-10 days) and valacyclovir (1000 mg twice daily for 7-10 days) are associated with significant reductions in virus shedding, symptoms, and time to healing (Kimberlin and Rouse, 2004). Intravenous acyclovir (5 mg/kg every 8 hours) has similar effects in patients hospitalized with severe primary genital HSV infections. Topical acyclovir is much less effective than systemic administration. None of these regimens reproducibly reduces the risk of recurrent genital lesions. Acyclovir (200 mg five times daily or 400 mg three times daily for 5 days or 800 mg three times daily for 2 days) or valacyclovir (500 mg twice daily for 3 or 5 days) shortens the manifestations of recurrent genital HSV episodes by 1-2 days. Frequently recurring genital herpes can be suppressed effectively with chronic oral acyclovir (400 mg twice daily or 200 mg three times daily) or with valacyclovir (500 mg or, for very frequent recurrences, 1000 mg once daily). During use, the rate of clinical recurrences decreases by ~90%, and subclinical shedding is markedly reduced, although not eliminated. Valacyclovir suppression of genital herpes reduces the risk of transmitting infection to a susceptible partner by ~50% over an 8-month period (Corey et al., 2004). Chronic suppression may be useful in those with disabling recurrences of herpetic whitlow or HSV-related erythema multiforme.
Oral acyclovir is effective in primary herpetic gingivostomatitis (600 mg/m2 four times daily for 10 days in children) but provides only modest clinical benefit in recurrent orolabial herpes. Short-term, high-dose valacyclovir (2 g twice over 1 day) shortens the duration of recurrent orolabial herpes by ~1 day (Elish et al., 2004). The FDA has approved an acyclovir/hydrocortisone combination (lipsovir) for early treatment of recurrent herpes cold sores. Topical acyclovir cream is modestly effective in recurrent labial (Spruance et al., 2002) and genital herpes simplex virus infections. Preexposure acyclovir prophylaxis (400 mg twice daily for 1 week) reduces the overall risk of recurrence by 73% in those with sun-induced recurrences of HSV infections. Acyclovir during the last month of pregnancy reduces the likelihood of viral shedding and the frequency of cesarean delivery in women with primary or recurrent genital herpes (Corey and Wald, 2009).
In immunocompromised patients with mucocutaneous HSV infection, intravenous acyclovir (250 mg/m2 every 8 hours for 7 days) shortens healing time, duration of pain, and the period of virus shedding. Oral acyclovir (800 mg five times per day) and valacyclovir (1000 mg twice daily) for 5-10 days are also effective. Recurrences are common after cessation of therapy and may require long-term suppression. In those with very localized labial or facial HSV infections, topical acyclovir may provide some benefit. Intravenous acyclovir may be beneficial in viscerally disseminating HSV in immunocompromised patients and in patients with HSV-infected burn wounds.
Systemic acyclovir prophylaxis is highly effective in preventing mucocutaneous HSV infections in seropositive patients undergoing immunosuppression. Intravenous acyclovir (250 mg/m2 every 8-12 hours) begun prior to transplantation and continuing for several weeks prevents HSV disease in bone marrow transplant recipients. For patients who can tolerate oral medications, oral acyclovir (400 mg five times daily) is effective, and long-term oral acyclovir (200-400 mg three times daily for 6 months) also reduces the risk of VZV infection (Steer et al., 2000). In HSV encephalitis, acyclovir (10 mg/kg every 8 hours for a minimum of 10 days) reduces mortality by >50% and improves overall neurologic outcome compared with vidarabine. Higher doses (15-20 mg/kg every 8 hours) and prolonged treatment (up to 21 days) are recommended by many experts. Intravenous acyclovir (20 mg/kg every 8 hours for 21 days) is more effective than lower doses in viscerally invasive neonatal HSV infections (Kimberlin et al., 2001). In neonates and immunosuppressed patients and, rarely, in previously healthy persons, relapses of encephalitis following acyclovir may occur. The value of continuing long-term suppression with valacyclovir after completing intravenous acyclovir is under study.
An ophthalmic formulation of acyclovir (not available in the U.S.) is at least as effective as topical vidarabine or trifluridine in herpetic keratoconjunctivitis.
Infection owing to resistant HSV is rare in immunocompetent persons; however, in immunocompromised hosts, acyclovir-resistant HSV isolates can cause extensive mucocutaneous disease and, rarely, meningoencephalitis, pneumonitis, or visceral disease. Resistant HSV can be recovered from 6-17% of immunocompromised patients receiving acyclovir treatment (Bacon et al., 2003). Recurrences after cessation of acyclovir usually are due to sensitive virus but may be due to acyclovir-resistant virus in AIDS patients. In patients with progressive disease, intravenous foscarnet therapy is effective, but vidarabine is not (Chilukuri and Rosen, 2003).
Varicella-Zoster Virus Infections. If begun within 24 hours of rash onset, oral acyclovir has therapeutic effects in varicella of children and adults. In children weighing up to 40 kg, acyclovir (20 mg/kg, up to 800 mg per dose, four times daily for 5 days) reduces fever and new lesion formation by ~1 day. Routine use in uncomplicated pediatric varicella is not recommended but should be considered in those at risk of moderate-to-severe illness (persons >12 years of age, secondary household cases, those with chronic cutaneous or pulmonary disorders, or those receiving corticosteroids or long-term salicylates) (Committee on Infectious Diseases, American Academy of Pediatrics, 2003). In adults treated within 24 hours, oral acyclovir (800 mg five times daily for 7 days) reduces the time to crusting of lesions by ~2 days, the maximum number of lesions by one-half, and the duration of fever. Intravenous acyclovir appears to be effective in varicella pneumonia or encephalitis of previously healthy adults. Oral acyclovir (10 mg/kg four times daily) given between 7 and 14 days after exposure may reduce the risk of varicella.
In older adults with localized herpes zoster, oral acyclovir (800 mg five times daily for 7 days) reduces pain and healing times if treatment can be initiated within 72 hours of rash onset. A reduction in ocular complications, particularly keratitis and anterior uveitis, occurs with treatment of zoster ophthalmicus. Prolonged acyclovir and concurrent prednisone for 21 days speed zoster healing and improve quality-of-life measures compared with each therapy alone. Valacyclovir (1000 mg three times daily for 7 days) provides more prompt relief of zoster-associated pain than acyclovir in older adults (≥50 years) with zoster.
In immunocompromised patients with herpes zoster, intravenous acyclovir (500 mg/m2 every 8 hours for 7 days) reduces viral shedding, healing time, and the risks of cutaneous dissemination and visceral complications, as well as the length of hospitalization, in disseminating zoster. In immunosuppressed children with varicella, intravenous acyclovir decreases healing time and the risk of visceral complications.
Acyclovir-resistant VZV isolates uncommonly have been recovered from HIV-infected children and adults who may manifest chronic hyperkeratotic or verrucous lesions and sometimes meningoradiculitis. Intravenous foscarnet also appears to be effective for acyclovir-resistant VZV infections.
Other Viruses. Acyclovir is ineffective therapeutically in established cytomegalovirus (CMV) infections but ganciclovir is effective for CMV prophylaxis in immunocompromised patients. High-dose intravenous acyclovir (500 mg/m2 every 8 hours for 1 month) in CMV-seropositive bone marrow transplant recipients is associated with ~50% lower risk of CMV disease and, when combined with prolonged oral acyclovir (800 mg four times daily through 6 months), improves survival. Following engraftment, valacyclovir (2000 mg four times daily to day 100) appears as effective as intravenous ganciclovir prophylaxis in such patients (Winston et al., 2003). High-dose oral acyclovir or valacyclovir (2000 mg four times daily) suppression for 3 months may reduce the risk of CMV disease and its sequelae in certain solid-organ transplant recipients (Lowance et al., 1999), but oral valganciclovir is the preferred agent for mismatched graft recipients (Pereyra and Rubin, 2004). Compared with acyclovir, high-dose valacyclovir reduces CMV disease in advanced HIV infection but is associated with greater toxicity and possibly shorter survival.
In infectious mononucleosis, acyclovir is associated with transient antiviral effects but no clinical benefits. EBV-related oral hairy leukoplakia may improve with acyclovir. Oral acyclovir in conjunction with systemic corticosteroids appears beneficial in treating Bell's palsy, but valacyclovir is ineffective in acute vestibular neuritis.