Untoward Effects

Acyclovir generally is well tolerated. Topical acyclovir may cause mucosal irritation and transient burning when applied to genital lesions.

Oral acyclovir infrequently is associated with nausea, diarrhea, rash, or headache and very rarely with renal insufficiency or neurotoxicity. Valacyclovir also may cause headache, nausea, diarrhea, nephrotoxicity, and CNS symptoms. High doses of valacyclovir have been associated with confusion and hallucinations, nephrotoxicity, and uncommonly, severe thrombocytopenia, 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 is recognized in infants born to women exposed to acyclovir during pregnancy.

The principal dose-limiting toxicities of intravenous acyclovir are renal insufficiency and CNS side effects. Preexisting renal insufficiency, high doses, and acyclovir plasma levels >25 mg/mL are risk factors for both. Reversible renal dysfunction occurs in ~5% of patients, likely related to crystal-luria. Manifestations include nausea and vomiting, flank pain, and 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. Neuro-toxicity occurs in 1-4% of patients and can cause altered sensorium, tremor, myoclonus, delirium, seizures, or extrapyramidal signs. Phlebitis following extravasation, rash, diaphoresis, nausea, hypotension, and interstitial nephritis also may occur. Hemodialysis may be useful in severe cases.

Severe somnolence and lethargy may occur with combinations of zidovudine and acyclovir. Concomitant cyclosporine enhances nephrotoxicity. Probenecid decreases acyclovir renal clearance and prolongs the plasma t1/2 of elimination. Acyclovir may decrease the renal clearance of other drugs eliminated by active renal secretion (e.g., 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. These drugs are particularly useful in immunocompromised patients because these individuals experience more frequent and more severe HSV and VZV infections. Since VZV is less susceptible than HSV to acyclovir, higher doses must be used for treating varicella or zoster 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) significantly reduce virus shedding, symptoms, and time to healing. Intravenous acyclovir (5 mg/kg every 8 hours) has similar effects in patients hospitalized with severe primary genital HSV infections. Topical acy-clovir is much less effective. None of these regimens reproducibly reduces the risk of recurrent genital lesions. Patient-initiated 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. Recurring genital herpes can be suppressed by chronic oral acyclovir (400 mg twice daily or 200 mg three times daily) or valacyclovir (500 mg or, for very frequent recurrences, 1000 mg once daily). The rate of recurrences decreases by ~90% during use, and subclinical shedding is markedly reduced, such that valacyclovir suppression of genital herpes reduces the risk of transmission to a susceptible partner by ~50% over an 8-month period.

Oral acyclovir is effective in primary herpetic gingivostomatitis (600 mg/m2 four times daily for 10 days in children) but has only modest benefit in recurrent orolabial herpes. High-dose vala-cyclovir (2 g twice over one day) shortens the duration of recurrent orolabial herpes by ~1 day. Topical acyclovir is modestly effective in recurrent labial and genital herpes simplex virus infections. Acyclovir prophylaxis (400 mg twice daily for one week) reduces the 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 frequency of cesarean section in women with primary or recurrent genital herpes.

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 drug cessation and may require long-term suppression. In those with very localized labial or facial HSV infections, topical acy-clovir 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 HSVinfections 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. In HSV encephalitis, acyclovir (10 mg/kg every 8 hours for at least 10 days) reduces mortality by >50% and improves neurological outcome. 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. In neonates and immunosuppressed patients and, rarely, in previously healthy persons, relapses of encephalitis following acyclovir may occur.

An ophthalmic formulation of acyclovir (not available in the U.S.) is effective in herpetic keratoconjunctivitis.

Infection owing to resistant HSV is rare in immunocompetent persons; in immunocompromised hosts, resistant HSV isolates can cause extensive mucocutaneous disease and, rarely, meningoencephalitis, pneumonitis, or visceral disease. Resistant HSV can be recovered from 6% to 17% of immunocompromised patients receiving acyclovir treatment. Recurrences after acy-clovir cessation 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.

Varicella-Zoster Virus Infections

If begun within 24 hours of rash onset, oral acyclovir is efficacious 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. Such use should be considered in those at risk of moderate-to-severe illness (persons >12 years old, secondary household cases, those with chronic cutaneous or pulmonary disorders, or those receiving glucocorticoids or long-term salicylates). 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 50%, and duration of fever. Intravenous acyclovir is 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 initiated within 72 hours of rash onset. Treatment of zoster ophthalmicus reduces ocular complications. Prolonged acyclovir and concurrent prednisone for 21 days speed zoster healing and improve quality-of-life compared with either therapy alone. Valacyclovir (1000 mg three times daily for 7 days) provides more rapid relief of zoster-associated pain than acyclovir in adults over 50 with zoster.

In immunocompromised patients with herpes zoster, intravenous acyclovir (500 mg/m2 every 8 hours for 7 days) reduces viral shedding, healing time, risks of cutaneous dissemination and visceral complications, and the length of hospitalization. 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 appears to be effective for acyclovir-resistant VZV infections.

Other Viruses

Acyclovir is ineffective in established CMV infections but has been used for CMV prophylaxis in immunocompromised patients. High-dose intravenous acyclovir (500 mg/m2 every 8 hours for one 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. High-dose oral acy-clovir or valacyclovir (2000 mg four times daily) suppression for 3 months may reduce the risk of CMV disease and its sequelae in some solid-organ transplant recipients, but oral valganciclovir is preferred. Compared with acyclovir, high-dose valacyclovir reduces CMV disease in advanced HIV infection but is associated with greater toxicity and possibly shorter survival.

Cidofovir chemistry and antiviral activity Cidofovir (1-[(S)-3-hydroxy-2-(phospho-nomethoxy)-propyl]cytosine dihydrate) is a cytidine nucleotide analog with inhibitory activity against human herpes, papilloma, polyoma, pox, and adenoviruses.

Cidofovir is a phosphonate that is phosphorylated by cellular but not virus enzymes. It inhibits acyclovir-resistant TK-deficient or TK-altered HSV or VZV strains, ganciclovir-resistant CMV strains with UL97 mutations, but not those with DNA polymerase mutations, and some foscarnet-resistant

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