Table 16-24 summarizes information on common antiviral drugs.
Systemic antiviral drugs
Acyclovir is a synthetic guanosine analogue. Because the viral thymidine kinase in HSV types 1 and 2 has much more affinity to acyclovir than does host thymidine kinase, high concentrations of acyclovir monophosphate accumulate in infected cells. Acyclovir monophosphate is then further phosphorylated to the active compound acyclovir triphosphate, which cannot cross cell membranes and accumulates further.
Acyclovir-resistant thymidine kinase HSVs have evolved. They occur primarily in patients receiving multiple courses of therapy or in patients with human immunodeficiency virus (HIV) infection. Thymidine kinase mutants are susceptible to vidarabine and foscarnet. Changes in viral DNA polymerase structures can also mediate resistance to acyclovir.
Oral acyclovir is only 15%–30% bioavailable, and food does not affect absorption. For unknown reasons, bioavailability is lower in patients with transplants. The drug is well distributed; cerebrospinal fluid (CSF) and brain concentrations equal approximately 50% of serum values. Concentrations of acyclovir in zoster vesicle fluid are equivalent to those in plasma. Aqueous humor concentrations are 35% those of plasma, and salivary concentrations are 15%. Vaginal concentrations are equivalent to those of plasma, and breast milk concentrations exceed them.
For adults and neonates with normal renal function, the plasma half-lives of acyclovir are 3.3 and 3.8 hours, respectively. The half-life increases to 20 hours in patients who are anuric. Acyclovir may interfere with the renal excretion of drugs that are eliminated through the renal tubules (eg, methotrexate); probenecid significantly decreases the renal excretion of acyclovir. This drug is effectively removed by hemodialysis (60% decrease in plasma concentrations following a 6-hour dialysis period) but only minimally removed by peritoneal dialysis.
Acyclovir is used off-label for ocular HSV and herpes zoster virus (HZV) but has proven effective in preventing the recurrence of HSV epithelial and stromal keratitis with twice-daily oral doses of 400 mg. Although this prophylactic dosage was originally studied over a 1-year treatment period, clinicians are using this dosage indefinitely to decrease the likelihood of disease recurrence. Similar dosing of acyclovir has proven beneficial in reducing the likelihood of recurrent herpetic eye disease after corneal transplantation. However, oral acyclovir was not beneficial when used with topical steroids and trifluridine in the treatment of active HSV stromal keratitis. The addition of oral acyclovir to a regimen of topical antiviral drugs may be considered for patients with HSV iridocyclitis. Although the benefit of this drug did not reach statistical significance in one study, participant enrollment had been halted because of inadequate numbers of patients.
Acyclovir is well tolerated in oral form, but parenteral acyclovir can cause renal toxicity due to crystalline nephropathy. Neurotoxicity may also occur with intravenous use. A commonly used intravenous dosage for acyclovir is 1500 mg/m2 per day.
Valacyclovir is currently approved for management of HZV infections in immunocompetent persons but not for HSV. It is an amino-acid ester prodrug of acyclovir; its bio-availability is much higher than that of acyclovir (54% vs 20%, respectively). Valacyclovir has been associated with nephrotoxicity and thrombocytopenia in immunocompromised patients.
Famciclovir is the oral prodrug of penciclovir and is currently approved for the management of uncomplicated acute HSV. Penciclovir, like acyclovir, requires phosphorylation by viral thymidine kinase to become active. It has demonstrated efficacy in relieving acute zoster signs and symptoms and reducing the duration of postherpetic neuralgia when administered during acute HZV.
Ganciclovir (9-2-hydroxypropoxymethylguanine) is a synthetic guanosine analogue active against many herpesviruses. It is approved for CMV retinitis and for CMV prophylaxis in patients with advanced HIV infection and in patients undergoing a transplant. Like acyclovir, it must be phosphorylated to become active. Infection-induced kinases, viral thymidine kinase, or deoxyguanosine kinase of various herpesviruses can catalyze this reaction. After monophosphorylation, cellular enzymes convert ganciclovir to the triphosphorylated form, and the triphosphate inhibits viral DNA polymerase rather than cellular DNA polymerase. Because of ganciclovir’s toxicity and the availability of acyclovir for treatment of many herpesvirus infections, the use of ganciclovir is currently restricted to treatment of CMV.
Systemic ganciclovir is used primarily intravenously because less than 5% of an oral dose is absorbed. CSF concentrations are approximately 50% of plasma concentrations; peak plasma concentrations reach 4–6 µg/mL. The plasma half-life is 3–4 hours in people with normal renal function, increasing to more than 24 hours in patients with severe renal insufficiency. More than 90% of systemic ganciclovir is eliminated unchanged in urine, and dose modifications are necessary for individuals with compromised renal function. Approximately 50% of ganciclovir is removed by hemodialysis. Bone marrow suppression is the primary adverse effect of systemic therapy. Periodic complete blood counts and platelet counts are required during the course of treatment. Ganciclovir can also be administered intravitreally.
Valganciclovir is a prodrug for ganciclovir that offers significantly higher bioavailability (60%) than ganciclovir (9%) when taken orally. After oral administration, it is rapidly converted to ganciclovir by intestinal and hepatic esterases. It can be used during the induction and/or maintenance phase of treatment in patients with CMV retinitis, affording them an outpatient alternative to ganciclovir.
Foscarnet (phosphonoformic acid) inhibits DNA polymerases, RNA polymerases, and reverse transcriptases. In vitro, it is active against herpesviruses, the influenza virus, and HIV. Foscarnet is approved for the treatment of HIV-infected patients with CMV retinitis and for acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients. It also inhibits CMVs that are resistant to acyclovir and ganciclovir. Foscarnet acts by blocking the pyrophosphate receptor site of CMV DNA polymerase. Viral resistance is attributable to structural alterations in this enzyme.
Foscarnet bioavailability is approximately 20%. Because it can bind with calcium and other divalent cations, foscarnet becomes deposited in bone and may be detectable for many months; 80%–90% of the administered dose appears unchanged in the urine. It is administered intravenously in doses adjusted for renal function and with hydration to establish sufficient diuresis. Treatment may be limited by nephrotoxicity in up to 50% of patients; other adverse effects include hypocalcemia and neurotoxicity. To limit systemic adverse effects, foscarnet can also be administered intravitreally.
Cidofovir is the third medication approved by the FDA for the treatment of CMV retinitis, and it is approved only for that use. Cidofovir is a cytidine nucleoside analogue that is active against herpesviruses, poxviruses, polyomaviruses, papillomaviruses, and adenoviruses. The drug is the second-line therapy for complications after smallpox vaccination (vaccinia virus) and has been used in selected studies for varicella-zoster retinitis, as well as adenoviral keratoconjunctivitis.
The mechanism of action of cidofovir is inhibition of DNA synthesis, and resistance is achieved through mutations in DNA polymerase. The prolonged intracellular half-life of an active metabolite allows once-weekly dosing during induction, with dosing every 2 weeks thereafter. Cidofovir does not have direct cross-resistance with acyclovir, ganciclovir, or foscarnet, although some virus isolates may have multiple resistances and may even develop triple resistance. In a small series of patients, cidofovir inhibited CMV replication when administered intravitreally. Long-lasting suppression of CMV retinitis was observed; the average time to progression was 55 days.
The primary adverse effect of cidofovir is renal toxicity, which can be decreased by intravenous prehydration and by both pretreatment and posttreatment with high-dose probenecid. Ocular adverse effects include uveitis and irreversible hypotony.
Zidovudine is a thymidine nucleoside analogue with activity against HIV. Zidovudine becomes phosphorylated to monophosphate, diphosphate, and triphosphate forms by cellular kinases in infected and uninfected cells. It has 2 primary methods of action:
The triphosphate acts as a competitive inhibitor of viral reverse transcriptase.
The azido group prevents further chain elongation and acts as a DNA chain terminator.
Zidovudine inhibits HIV reverse transcriptase at much lower concentrations than needed to inhibit cellular DNA polymerases.
Since the introduction of zidovudine in the 1980s, numerous antiretroviral drugs have been approved for the treatment of HIV infection. They are divided into 6 classes: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, entry inhibitors, and integrase strand transfer inhibitors. The current standard antiretroviral therapy (ART) consists of a combination of antiretroviral drugs.
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Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.