Acyclovir is active against herpes simplex virus and varicella-zoster virus. In herpes-infected cells, it is selectively active against viral DNA polymerase and thus inhibits virus proliferation. Given intravenously (15 mg/kg/day in three divided doses), it is useful in the treatment of mucocutaneous herpes simplex in immunocompromised patients. It can reduce pain, accelerate healing, and prevent dissemination of herpes zoster and varicella in immunocompromised patients. The usual dosage for serious varicella-zoster infections is greater, ie, 30 mg/kg/day intravenously in three equal doses. The medication has no effect on establishment of latency or frequency of recurrence. A 2014 Cochrane review concluded that oral acyclovir does not significantly reduce the incidence of postherpetic neuralgia. Acyclovir (30 mg/kg/day intravenously in three equal doses) is the medication of choice for herpes encephalitis. Intravenous or oral acyclovir is effective prophylaxis against recurrent mucocutaneous and visceral herpes infections in transplant and other severely immunosuppressed patients. Prophylactic intravenous or oral acyclovir is effective in preventing cytomegalovirus (CMV) disease in some transplant settings (kidney and perhaps bone marrow) but not in others (liver).
Oral acyclovir, 400 mg three times daily for 7–10 days, is effective in primary genital herpes simplex infections. Oral acyclovir at a dose of 800 mg three times a day for 2 days for recurrent genital herpes reduces viral shedding and symptoms. Suppressive therapy (400 mg twice daily) for 4–6 months reduces the frequency and severity of recurrent genital herpetic lesions. Acyclovir minimally affects symptoms or viral shedding in recurrent herpes labialis and is not generally used for this disease. However, in a dose of 400 mg twice daily, it is effective in preventing recurrent herpes labialis in those with frequent relapses and in preventing sun-induced relapses.
Other uses of oral acyclovir include (1) acceleration of healing of herpes zoster in immunocompetent patients if initiated within 48 hours after onset (800 mg five times daily for 7 days), (2) more rapid healing of rash and lessened clinical symptoms of primary varicella in adults and children if instituted within 24 hours after onset of rash and continued for 5–7 days, (3) prevention of herpes simplex and CMV infections in transplant recipients (in doses of 800 mg four or five times daily), and (4) prophylaxis against varicella in susceptible household contacts.
Topical 5% acyclovir ointment can shorten the period of pain and viral shedding in herpes simplex mucocutaneous oral lesions in immunosuppressed patients but not in patients with normal immunity. In contrast, acyclovir cream or penciclovir ointment (see famciclovir, below) appears to reduce the duration of pain and viral shedding by approximately 1 day in immunocompetent patients. Oral acyclovir is significantly more efficacious than topical therapy for this indication.
The absolute oral bioavailability of acyclovir is 10–30%. Famciclovir and valacyclovir (see below) are significantly better absorbed than oral acyclovir and can be administered less frequently. Dosage reduction in kidney disease is required. Since hemodialysis reduces serum levels significantly, the daily dose should be given after hemodialysis.
Acyclovir is relatively nontoxic. Precipitation of medication in renal tubules has been described with intravenous acyclovir and can be avoided by maintaining adequate hydration and urine flow. Resistance has been described, usually in immunosuppressed patients who have received multiple courses of therapy.
Famciclovir is a prodrug of penciclovir. After oral administration, 75–80% is absorbed and deacetylated in the intestinal wall to the active drug, penciclovir. Penciclovir, like acyclovir, inhibits viral replication by interfering with viral DNA polymerase. Acyclovir-resistant strains of herpes simplex and varicella-zoster virus are also resistant to famciclovir. Famciclovir in a dose of 500 mg three times daily for 7 days accelerates healing of lesions in acute herpes zoster if started within 72 hours after the onset of rash. At a dose of 125 mg twice daily for 5 days, famciclovir is effective therapy of recurrent genital herpes; at a dose of 500 mg twice daily, it is effective as chronic suppressive therapy.
Valacyclovir is a prodrug of acyclovir that has significantly increased oral bioavailability when compared with acyclovir. After absorption, it is converted to acyclovir and serum levels are three to five times higher than those achieved with acyclovir. Valacyclovir at a dosage of 1 g three times daily for 7–10 days is effective therapy for herpes zoster when started within 72 hours after onset of rash and is slightly more effective than acyclovir in relieving zoster-associated pain. It shortens the course of initial episodes of genital herpes (1 g twice daily for 7–10 days), can be used to treat recurrent genital herpes (500 mg twice daily for 3 days), and is effective prophylaxis for recurrent genital herpes when given as a single 1-g daily dose. Valacyclovir prophylaxis (500 mg daily) reduces the rate of viral shedding and transmission of herpes in discordant monogamous couples. At doses of 2 g four times daily, valacyclovir is more effective than placebo in preventing CMV infections in seronegative recipients of a kidney from a seropositive donor. The adverse effect profile of valacyclovir is comparable to that of acyclovir.
Foscarnet (trisodium phosphonoformate) is a pyrophosphate analog that inhibits viral DNA polymerase of human herpesviruses (CMV, herpes simplex, varicella-zoster) and the reverse transcriptase of HIV. The medication is much less well tolerated than acyclovir and ganciclovir and more difficult to administer. Therefore, its use is limited to patients who do not respond to or cannot tolerate ganciclovir or acyclovir. Isolates of ganciclovir-resistant CMV and acyclovir-resistant herpes simplex and varicella-zoster usually are susceptible to foscarnet. Oral absorption is poor, and the medication must be given intravenously. The half-life is 3–5 hours, and this is prolonged with kidney disease. The usual induction dose is 60 mg/kg/dose every 8 hours, and the dose for maintenance therapy is 120 mg/kg once daily. Adjustments are required for even minimal impairment in kidney function (see package insert).
Foscarnet can cause severe phlebitis; thus, central intravenous administration is generally used. Nephrotoxicity, which is dose-dependent and reversible, is the major toxicity. Prehydration with 2.5 L of 0.9% saline reduces nephrotoxicity. Foscarnet binds divalent cations, and hypocalcemia, peripheral neuropathy, seizures and arrhythmias, hypomagnesemia, and hypophosphatemia can occur. Monitoring of electrolytes and kidney function is required during therapy. Anemia (20–50%) and nausea and vomiting (20–30%) are other common adverse effects.
Cidofovir is a nucleotide analog that is active against almost all human herpesviruses and poxviruses. The medication has a prolonged pharmacokinetic intracellular half-life, allowing for administration every 1–2 weeks. Strains of CMV, herpes simplex virus, and herpes zoster virus that are resistant to ganciclovir or acyclovir often are susceptible to cidofovir. However, the least likely cross-resistance is between foscarnet and cidofovir. Cidofovir delays progression of CMV retinitis in newly diagnosed disease (5 mg/kg weekly for 2 weeks, followed by maintenance of 3–5 mg/kg every other week) and is effective therapy in relapsed disease or in patients who are intolerant of traditional therapy (5 mg/kg every other day). The medication is ineffective or only marginally effective in the treatment of AIDS-associated progressive multifocal leukoencephalopathy. Cidofovir is associated with a high incidence of nephrotoxicity, sometimes severe. To avoid this complication, probenecid, an inhibitor of active tubular secretion, and intravenous saline must be administered with each dose. Ocular toxicity, including uveitis and iritis, is another complication reported with cidofovir.
Ganciclovir is an analog of acyclovir with similar antiviral activity, including activity against CMV. The addition of intravenous immunoglobulin or CMV immune globulin to ganciclovir may improve outcomes associated with CMV pneumonitis in bone marrow transplant patients. Ganciclovir is frequently used in solid organ and stem cell transplant patients in the treatment and prevention of infection. However, there is no uniformity of opinion about the duration of therapy or the route of administration. Before the availability of oral valganciclovir (see below), which results in serum levels equivalent to those achieved with intravenous medication, ganciclovir was frequently administered intravenously and in the immediate posttransplant period for 1–2 weeks. Depending on the type of transplant (bone marrow transplant patients are at greater risk for developing CMV disease than solid organ transplant patients) and the serologic status of the donor and recipient (seronegative recipients who receive solid organ transplants from seropositive donors are at greatest risk for developing disease), various antiviral agents are used to prevent infection. Acyclovir, valacyclovir, ganciclovir, and valganciclovir have been used in the prevention of CMV in stem cell transplant patients. With the availability of oral valganciclovir, high-risk patients can benefit from prophylaxis without relying on the use of the intravenous route. In addition, because tests to detect early infection with CMV are very sensitive, the strategy for prevention has shifted from one of universal prophylaxis to one of preemptive therapy. At many institutions, high-risk patients are routinely screened for CMV DNA in blood by antigen detection or polymerase chain reaction. A positive test results in subsequent preemptive therapy with intravenous ganciclovir or oral valganciclovir.
The major adverse effect is neutropenia, which is reversible but may require the concomitant use of colony-stimulating factors. Thrombocytopenia, nausea, rash, and phlebitis occur less commonly.
Oral ganciclovir is no longer marketed, and it has been replaced by valganciclovir, an esterification product of ganciclovir that is significantly better absorbed. Administration of 900 mg of valganciclovir orally results in serum ganciclovir levels equal to those achieved with an intravenous 5 mg/kg dose of ganciclovir. In CMV retinitis in AIDS patients, oral valganciclovir is as efficacious as intravenous ganciclovir therapy.
Letermovir is a CMV DNA terminase complex inhibitor approved for CMV prophylaxis in allogeneic hematopoietic stem cell transplant recipients up to 100 days posttransplant. Compared with placebo, letermovir therapy results in significantly fewer CMV infections within 6 months of allogeneic hematopoietic stem cell transplantation. Letermovir is administered as an intravenous infusion at 480 mg once daily. As an inhibitor of CYP3A, letermovir can increase concentrations of CYP3A substrates such as amiodarone, HMG-CoA reductase inhibitors, and immunosuppressants such as cyclosporine, tacrolimus, and sirolimus. Letermovir also induces CYP2C9 and 2C19 as well as inhibits hepatic organic anion transporters that are responsible for uptake of certain medications. Since letermovir is also a substrate of many drug enzymes, including CYP3A4, letermovir concentrations can be affected by CYP inducers/inhibitors (eg, cyclosporine, rifampin). A dose reduction from 480 mg to 240 mg once daily is recommended if cyclosporine is coadministered with letermovir. Patients receiving letermovir should be closely evaluated for drug interactions. Compared to other available CMV prophylaxis agents (eg, valganciclovir), letermovir appears to cause little myelosuppression. The most common side effects of letermovir, compared to placebo, are vomiting, edema, and atrial fibrillation or flutter.