Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

  • Drugs Used in treating Herpes Viral Infections and related agents

    • IV cidofovir has been approved for use in CMV (cytomegalovirus) retinitis in AIDS patients intolerant of ganciclovir (Cytovene) or foscarnet or in those patients in which these drugs have been therapeutically ineffective.

      • Intravitreal cidofovir exhibits notable toxicity when used to treat CMV retinitis.

    • Fomivirsen (Vitavene) is an antisense oligonucleotide, FDA approved in humans in 1998 but subsequently discontinued in the U.S.⁵  

      • The reason of its discontinuation in the U.S. may be related to the decline in incidence of CMV retinitis due to the highly active antiretroviral drug therapies.⁵  

      •  

        Fomivirsen (Vitavene): Antisense Oligonucleotide⁴

        Left: Skeletal formula Center:  Ball-and-stick model Right:  Space-filling model4

        • This agent is a phosphorothioate oligonucleotide that inhibits CMV (cytomegalovirus) replication as a result of interacting with CMV mRNA.

          • The phosphorothioate linkage confers resistance to nuclease degradation.

          • The sequences of the 21 member oliogucleotide is:  5'-GCG TTT GCT CTT CTT CTT GCG-3'

        • The fomivirsen oligonucleotide sequence exhibits complementarity to the CMV message transcripts of the "major intermediate early region 2" (IE2).

          • This region codes for proteins associated with viral gene expression and fomivirsen binding here inhibits protein synthesis and CMV replication.⁵ 

        • The preceding describes the "antisense" mechanism of action.

          • However, fomivirsen may also inhibit CMV by interfering with viral absorption to cells as well as by direct viral replication inhibition.

        • Its unique mechanism of action accounts for fomivirsen antiviral activity with respect to CMV isolates resistant to nucleoside or nucleotide analogues including ganciclovir, foscarnet, or cidofovir.

          • Fomivirsen has been FDA approved for intravitreal administration for treatment of CMV retinitis in those patients not responding to the treatments are not being able to tolerate other treatments.

          • Primary toxicity is ocular inflammation such as vitreitis and iritis.

            • These reactions typically respond to topical glucocorticoid application.

    • Foscarnet (Foscavir)

      • Foscarnet (Foscavir)⁶

        Foscarnet blocks, non-competitively, the pyrophosphate binding site of viral DNA polymerase. This inhibition prevents both cleavage of pyrophosphate from deoxynucleotide triphosphate and viral DNA chain elongation. By contrast to drugs such as acyclovir, foscarnet does not require viral thymidine kinase for activation.6

      • Foscarnet (Foscavir) inhibits herpes virus replication including cytomegalovirus.²  

        • The target site for drug-mediated inhibition is DNA polymerase, at the pyrophosphate binding site.

        • This agent, by contrast to drugs such as acyclovir, does not require phosphorylation for activation.

          • Therefore, foscarnet is effective even against those herpes simplex virus (HSV) and varicella-zoster virus (VZV) isolates which are resistant to acyclovir due to low levels or absent levels of thymidine kinase.

          • Foscarnet is also effective against most ganciclovir-resistant cytomegalovirus (CMV) strains.

            • Additionally, foscarnet inhibits the HIV (human immunodeficiency virus) reverse transcriptase enzyme.²

      • Foscarnet has been used in management of CMV retinitis in AIDS patients and in the treatment of acyclovir-resistant mucocutaneous herpes simplex viral infections.²

        • In CMV retinitis patients,  foscarnet administration leads to clinical stabilization in about 90% of individuals.

          • Ganciclovir or foscarnet administration appear comparably effective in treating CMV retinitis in AIDS patients; however, overall survival appeared enhanced in the foscarnet-treated group.

            • This improves survival result may be related to foscarnet's inherent anti-HIV effect.

            • On the other hand, due to side effects, patients were much more compliant in adhering to their ganciclovir treatment compared to those receiving foscarnet.

            • In refractory retinitis the combination of foscarnet and ganciclovir appears more effective than either agent by itself for treating refractory retinitis.

            • Foscarnet may be useful in other AIDS-related CMV syndromes or transplantation-related CMV syndromes.

              • However, foscarnet does not appear clinically effective by itself in managing CMV pneumoniae in bone marrow transplant individuals.

          • Foscarnet, when employed for CMV infection treatment, may also decrease the likelihood of Kaposi's sarcoma in HIV-infected individuals.

            • Kaposi's Sarcoma¹¹

              Kaposi sarcoma is a tumor resulting from a viral infection due to human herpesvirus 8 (HHV8).  This disorder is also known as Kaposi's sarcoma-associated herpes virus (KSHV). In the 1990s Kaposi's sarcoma was described as the most common neoplasm occurring in persons with AIDS, noting that approximately 15 to 20% of AIDS patients develop this neoplasm.12  Epidemiological analysis suggested that AIDS-associated KS (AIDS-KS) might exhibit on infectious etiology. Molecular biological analysis was used to identify unique sequences present in more than 90% of Kaposi's sarcoma tissues, which had been obtained from patients with acquired immunodeficiency syndrome (AIDS). A technique termed "representational difference" was used to identify the presence of foreign DNA sequences, in this case belonging to an infectious agent in AIDS-KS. Unique sequences so identified were not found in 15% of non-KS tissue DNA samples from AIDS patients.12   Sequences that were associated with KS tissue DNA samples, due to foreign DNA sources, were homologous to capsid integument protein genes of Gammaherpesvirinae, herpes saimiri and Epstein-bar virus.12   Subsequent studies confirmed the presence of human herpesvirus 8 (HHV-8) in all Kaposi's sarcoma clinical variants as well is in two lymphoproliferative diseases: primary effusion lymphoma and multicentric Castleman's disease (MCD).13 Seroepidemiological studies have shown the link between HHV-8 infection in Kaposi's sarcoma development.13

            • In the case of acyclovir-resistant mucocutaneous HSV disease, lower foscarnet doses appear accompanied by cessation of viral shedding and lead to lesion healing most of the time (75%).

        • For the mechanistic reasons noted earlier, foscarnet has been used to treat acyclovir-resistant HSV and VZV infections in addition to ganciclovir-resistant CMV infections.

          • Some CMV isolates may be resistant to foscarnet.

        • The major toxicity associated with foscarnet is renal dysfunction, requiring close kidney monitoring.² 

          • Nephrotoxic effects and electrolyte disturbances may be mitigated by adequate hydration (saline) and slow drug infusion.

            • Evidence of nephrotoxicity include a reversible elevation in serum creatinine which may be noted in up to 50% of patients.¹ 

              • Risk factors for foscarnet toxicity include:¹

                • Higher dosages

                • High infusion rate

                • Dehydration

                • Pre-existing renal dysfunction and

                • Concurrent administration of nephrotoxic agents.

              • Manifestations of nephrotoxicity also include:¹

                • Acute tubular necrosis

                  • Acute Tubular Necrosis⁹

                    Attribution:  Minarcik JR  Histopathology Kidney:  Acute Tubular Necrosis https://www.youtube.com/watch?v=aM2TwOiI2Y4 (4/2007)

                • Nephrogenic diabetic insipidus

                • Crystalline glomerulopathy

                  •  

                    "Foscarnet-Induced Crystalline Glomerulonephritis"¹⁰

                    Left image:  "Crystalline precipitation within glomerular capillaries." Right image:  "Crystals stained black with Von Kossa's reaction." Image Attribution:  These figures correspond to Fig. 1A (left) and 1B (right) from reference 10

                • Interstitial nephritis.

              • Pre-drug administration of saline loading may be helpful in averting or mitigating foscarnet nephrotoxicity.¹ 

          • Symptomatic hypocalcemia may also accompany foscarnet administration.¹ 

            • Decreases in serum Ca²⁺ may result in:

              • Paresthesia

              • Tetany

              • Arrhythmias

              • Seizures, as well as

              • Other central nervous system (CNS) abnormalities.

            • Concurrent administration of pentamidine appears to increase the likelihood of symptomatic hypocalcemia.¹

        • By contrast to certain other antiviral agents, foscarnet is not notably myelosuppressive, allowing concurrent administration with myelosuppressive drugs including zidovudine (AZT).²

    • Trifluridine (Viroptic)²

      •  

        Trifluidine (Viroptic)

      • Trifluridine, a pyrimidine nucleoside, exhibits antiviral activity against HSV-1, HSV-2, and cytomegalovirus (CMV).²

        • Trifluridine monophosphate is an irreversible inhibitor of thymidylate synthetase.

        • Trifluridine triphosphate inhibits both viral and cellular DNA polymerases, inhibiting the viral enzyme to a greater extent.

        • Trifluridine has been approved for treating herpes simplex viral keratitis, HSV keratitis.²

          •  

            HSV Keratitis⁷

            "Herpes simplex dendritic epihelial keratitis"7

          • Trifluridine appears more effective when compared to topical idoxuridine while being comparably effective to topical vidarabine in this setting.² 

        • In certain cases topical trifluridine administration at sites of acyclovir-resistant HSV mucocutaneous infections may be helpful.²