Attachment to a cell receptor is a virus-specific event. Antibodies can bind to the extracellular virus and prevent this attachment. However, although therapy with antibody is useful in prophylaxis, it has been minimally effective in treatment.
Inhibitors of Cell Penetration and Uncoating
Amantadine and rimantadine are symmetric amines, which are thought to inhibit viral uncoating as their primary antiviral effect.
Rimantadine differs from amantadine by the substitution of a methyl group for a hydrogen ion. They are extremely selective, with activity against only influenza A, where they act as inhibitors of the viral M2 protein. They have been used either as prophylaxis or for therapy. Unfortunately, since 2001, the rates of resistance to amantadine/rimantadine have increased so sharply (up to 100% for some strains) that they are no longer routinely recommended.
Effective only against influenza A viruses, but sharply rising resistance rates now preclude their routine use
Pharmacology and Toxicity
Both amantadine and rimantadine are available only as oral preparations. The pharmacokinetics of the two agents is quite different. Amantadine is excreted by the kidney without being metabolized, and its dose must be decreased in patients with impaired renal function. In contrast, rimantadine is metabolized by the liver, then excreted in the kidney, and dosage adjustment for renal failure is not necessary. The major toxicity is in the CNS—seizures, somnolence, etc.
Rimantadine is metabolized by the liver
Amantadine is excreted by the kidney
Oseltamivir and zanamivir are antiviral agents that inhibit the neuraminidase of influenza A and B viruses. The neuraminidase cleaves terminal sialic acid from glycoconjugates and plays a role in the release of virus from infected cells. Zanamivir is given by inhalation using a specially designed device. Oseltamivir phosphate is the oral prodrug of oseltamivir, a drug comparable to zanamivir in antineuraminidase activity.
✺ Neuraminidase inhibitors are effective in treatment and prophylaxis of influenza A and B viruses
Treatment with either oseltamivir or zanamivir reduces influenza symptoms, shortens the course of illness by 0.5 to 1.5 days, and reduces the rate of complications.
Inhibitors of Nucleic Acid Synthesis
At present, most antiviral agents are nucleoside analogs that are active against virus-specific nucleic acid polymerases or reverse transcriptases and have much less activity against analogous host enzymes. Some of these agents serve as nucleic acid chain terminators after incorporation into nucleic acids.
Idoxuridine and Trifluorothymidine
Idoxuridine (5-iodo-2′-deoxyuridine, IUdR) is a halogenated pyrimidine that blocks nucleic acid synthesis by being incorporated into DNA in place of thymidine and producing a nonfunctional molecule. It is phosphorylated by cellular thymidine kinase to the active compound, which inhibits both viral and cellular DNA polymerase. The resulting host toxicity precludes systemic administration in humans. Idoxuridine can be used topically as effective treatment of herpetic infection of the cornea (keratitis). Trifluorothymidine, a related pyrimidine analog, is effective in treating herpetic corneal infections, including those that fail to respond to IUdR. Trifluorothymidine has largely replaced IUdR.
✺ Idoxuridine and trifluorothymidine block DNA synthesis
This antiviral agent differs from the nucleoside guanosine by having an acyclic (hydroxyethoxymethyl) side chain. The key to its benefit is that it must be phosphorylated by viral thymidine kinase to be active. Therefore, the compound is essentially nontoxic because it is not phosphorylated or activated in uninfected host cells. Viral thymidine kinase catalyzes the phosphorylation of acyclovir to a monophosphate. From this point, host cell enzymes complete the progression to the diphosphate and, finally, the triphosphate. Acyclovir triphosphate inhibits viral replication by competing with guanosine triphosphate and inhibiting the function of the virally encoded DNA polymerase. The selectivity and minimal toxicity of acyclovir is aided by its 100-fold or greater affinity for viral DNA polymerase than for cellular DNA polymerase. A second mechanism of viral inhibition results from incorporation of acyclovir triphosphate into the growing viral DNA chain. This causes termination of chain growth because there is no 3′-hydroxy group on the acyclovir molecule to provide attachment sites for additional nucleotides.
Activity of acyclovir against herpesviruses directly correlates with the capacity of the virus to induce a thymidine kinase. Susceptible strains of herpes simplex virus types 1 and 2 (HSV-1 and -2) are the most active thymidine kinase inducers and are the most readily inhibited by acyclovir. Cytomegalovirus (CMV) induces little or no thymidine kinase and is not inhibited. Varicella-zoster and Epstein-Barr viruses are between these two extremes in terms of both thymidine kinase induction and acyclovir susceptibility.
✺ Acyclovir is effective against the herpesviruses, which induce thymidine kinase
Resistant strains of HSV have been recovered from immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS); in most instances, resistance results from mutations in the viral thymidine kinase gene, rendering it inactive in phosphorylation. Resistance may also result from mutations in the viral DNA polymerase. Remarkably, resistant virus has rarely been recovered from immunocompetent patients, even after years of drug exposure and frequent usage.
✺ Acyclovir inhibits viral DNA polymerase and terminates viral DNA chain growth
Pharmacology and Toxicity
Acyclovir is available in three forms: topical, oral, and parenteral. Topical acyclovir is rarely used. The oral form has low bioavailability (~10%), but achieves concentrations in blood that inhibit HSV and, to a lesser extent, varicella-zoster virus (VZV). Intravenous acyclovir is used for serious HSV infection (eg, congenital, encephalitis) as well as for VZV infection in immunocompromised patients. Because acyclovir is excreted by the kidney, the dosage must be reduced in patients with renal failure. Central nervous system toxicity and renal toxicity have been reported in patients treated with prolonged high intravenous doses. Despite its mechanism of action acyclovir is remarkably free of bone marrow toxicity, even in patients with hematopoietic disorders—a feature attributable to the absence of its phosphorylation (ie, activation) in uninfected host cells.
Intravenous acyclovir used in serious HSV infections
Treatment and Prophylaxis
Acyclovir is effective in the treatment of primary HSV mucocutaneous infections or for severe recurrences in immunocompromised patients. The agent is useful in neonatal herpes and encephalitis, infection in immunocompromised patients and for varicella in older children or adults. Acyclovir is beneficial against herpes zoster in elderly patients or any patient with eye involvement. In patients with frequent severe genital herpes, the oral form is effective in preventing recurrences. Because it does not eliminate the virus from the host, it must be taken daily to be effective. Acyclovir is minimally effective in the treatment of recurrent genital or labial herpes in otherwise healthy individuals.
Valacyclovir, Famciclovir, and Penciclovir
Valacyclovir is a prodrug of acyclovir that is, better absorbed and, therefore, can be used in lower and less frequent dosage (bioavailability ~60%). When absorbed, it becomes acyclovir. It is currently approved for use in HSV and VZV infections. Dosage adjustment is necessary in patients with impaired renal function.
Famciclovir is similar to acyclovir in its structure and requirement for phosphorylation, but differs slightly in its mode of action. After absorption, the agent is converted to penciclovir, the active moiety, which inhibits viral DNA polymerase. However, it does not irreversibly terminate DNA replication. Famciclovir is currently approved for the treatment of HSV and VZV infections. Penciclovir is approved for topical treatment of recurrent herpes labialis.
Agents that are similar to or become acyclovir after absorption are available
Ganciclovir (DHPG), a nucleoside analog of guanosine, differs from acyclovir by a single carboxyl side chain. This structural change confers approximately 50 times more activity against CMV than acyclovir. Acyclovir has low activity against CMV because it is not well phosphorylated in CMV-infected cells due to the absence of the gene for thymidine kinase in CMV. However, ganciclovir is active against CMV because another viral-encoded phosphorylating enzyme (UL97) is present in CMV-infected cells that is, capable of phosphorylating ganciclovir and converting it to the monophosphate. Then, cellular enzymes convert it to the active compound, ganciclovir triphosphate, which inhibits the viral DNA polymerase (UL 54). Since ganciclovir can be phosphorylated in normal, uninfected, host cells, toxicity, especially neutropenia, frequently limits therapy. Discontinuation of therapy is necessary in patients whose neutrophils do not increase during dosage reduction or in response to cytokines. Thrombocytopenia (platelet count less than 20 000/mm3) occurs in approximately 15% of patients. Ganciclovir is also active against herpes simplex and VZ viruses but is not the drug of choice for these viruses due to toxicity.
Ganciclovir does not utilize viral thymidine kinase for phosphorylation
Oral ganciclovir is available, but is inferior to the intravenous form. Oral valganciclovir, a prodrug of ganciclovir, has improved bioavailability and is equivalent to the intravenous form.
Neutropenia and thrombocytopenia limit use
Administration of ganciclovir or valganciclovir is indicated for the prevention or treatment of active CMV infection in immunocompromised patients, but other herpesviruses (particularly HSV-1, HSV-2, and VZV) are also susceptible. Because patients with AIDS with severe CMV infection frequently have concurrent illnesses caused by other herpesviruses, treatment with ganciclovir may benefit associated HSV and VZV infections.
After several months of continuous ganciclovir therapy for treatment of CMV, between 5% and 10% of patients with AIDS excrete resistant strains of CMV. In almost all isolates, a mutation is found in the phosphorylating gene (UL97), and in a lesser number a mutation may also be found in the viral DNA polymerase (UL 54). Most of these strains remain sensitive to foscarnet, which may be used as an alternate therapy. If only a UL97 mutation is present, the strains remain susceptible to the nucleotide analog cidofovir (see later in chapter); however, if the CMV strain has a ganciclovir-induced mutation in DNA polymerase (UL 54), the virus is cross-resistant to cidofovir. Ganciclovir resistance has been noted in transplant recipients, in patients with lung or liver transplants, and those requiring prolonged prophylaxis or treatment.
CMV resistance increases with continuous therapy
Nucleotide Analogs: Cidofovir
The first example of the nucleotide analogs is cidofovir. This compound has a phosphonate group attached to the molecule and appears to the cell as a nucleoside monophosphate, in effect, a nucleotide. Cellular enzymes then add two phosphate groups to generate the active compound. In this form, the drug inhibits both viral and cellular nucleic acid polymerases, but selectivity is provided by its higher affinity for the viral enzyme.
✺ Cidofovir inhibits viral DNA polymerase
Nucleotide analogs do not require phosphorylation, or activation, by a viral-encoded enzyme and remain active against viruses that are resistant due to mutations in codons for these enzymes, for example, a UL97 mutant CMV. Resistance to cidofovir can, of course, develop with mutations in the viral DNA polymerase, UL54. An additional feature of cidofovir is a very prolonged half-life as a result of slow clearance by the kidneys.
Cidofovir is approved for intravenous therapy of CMV retinitis, and maintenance treatment may be given as infrequently as every 2 weeks. In addition, it is occasionally used to treat severe, disseminated adenovirus and BK virus infections although its efficacy for these is unproven. Nephrotoxicity is a serious complication of cidofovir treatment, and patients must be monitored carefully for evidence of renal impairment.