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Antiviral therapy

Antiviral therapy. E.McNamara. Challenges. Virus parasitize host cells Target the virus specifically Latency, quiescent phase Is treatment necessary? Efficacy of Rx. Current agents. Exploit viral : host replication Target viral DNA polymerases Accumulate in viral infected cells

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Antiviral therapy

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  1. Antiviral therapy E.McNamara

  2. Challenges • Virus parasitize host cells • Target the virus specifically • Latency, quiescent phase • Is treatment necessary? • Efficacy of Rx.

  3. Current agents • Exploit viral : host replication • Target viral DNA polymerases • Accumulate in viral infected cells • Activated by virus encoded enzymes • Dose related toxicity

  4. Acyclovir • Nucleoside analogue • Inhibits viral DNA polymerase • Stops replicating viral DNA chains • Excreted via renal • Serum half life 2-3 hrs • Good tissue distribution • Activated by HSV-TK to triphosphate form

  5. Acyclovir toxicities • CNS, • Confusion, seizures, coma. • Highest risk • Renal impairment • Old age • Prior mental disability • Potential teratogenicity • Resistance

  6. In-vitro HSV VZV EBV CMV In-vivo HSV VZV Acyclovir, uses

  7. Famciclovir • Nucleotide analogue • Similar spectrum to acyclovir • Similar mode of action • Inactive prodrug of penciclovir • Activated by viral-TK to penciclovir

  8. Famciclovir cont. • Greater bioavailability • Prolonged intracellular half-life • TID dosing

  9. Famciclovir toxicities • No major S/E • Potentially teratogenic • Potential male infertility • Levels increased by probenecid • May increase digoxin levels

  10. Valaciclovir • Valyl ester of acyclovir • P.O. metabolised to acyclovir • Plasma levels equivalent to IV acyclovir • Sustitute for IV acyclovir • Bioavailability dependant on GIT and hepatic function

  11. Valaciclovir • Toxicities similar to acyclovir • TTP in immunocompromised on prolonged Rx.

  12. Penciclovir • Nucleoside analogue • Similar activity to acyclovir • Topical, Herpes labialis.

  13. Herpes infection Rx. • Improved PO bioavailability • Different mode of action-resistance • Improved efficacy • Type, • Primary • Secondary/reactivation • Suppressive Rx. • Vaccines and immunomodulators

  14. Herpes Rx. • HSV • Herpes labialis • Genital herpes • Encephalitis • Immunocompromised • VZV • H.zoster • EBV

  15. Gangciclovir • Competively inhibits viral DNA polymerase • Incoporates into viral DNA, chain terminator • Major agent for CMV • Accumulates in CMV infected cells • Excreted renally • Crosses Blood Brain Barrior

  16. Gangciclovir, toxicity • Haematologic/bone marrow • Neutropaenia • Thrombocytopaenia • Interacts with cytotoxic drugs • Renal impairment • Carcinogenic • Potentiated by probenecid

  17. Foscarnet • Binds viral DNA polymerase and RT. • Active v Herpes viruses • Not curative • Excreted renally • Variable half-life • Impairs biochem. • Monitor u/e, creatinine

  18. Fomivirsen • Active v CMV • Inactivates CMV mRNA • Local, no systemic anti-CMV Rx. • Substitute for CMV retinitis Rx. • Intra-vitreal injections • S/E, intraocular pressure, retinal toxicity

  19. CMV management • Disseminated disease • Gangciclovir/Foscarnet/ • CMV-Iggs, pneumonitis BMT • Prophylaxis/preemptive in Tx. • Gangciclovir/acyclovir/valaciclovir • Retinitis • Formiversin/gangciclovir -local

  20. Amantadine • Inhibits Influ-A uncoating on host cell entry • Early Rx. Within 48hrs of symptoms • Prophylaxis of unimmunised high risk • Combined with vaccine until immunity develops • Renal excretion • Rapid resistance • S/E, CNS- dissyness, seizures

  21. Rimantadine • Structural analogue of amantadine • Fewer CNS S/E

  22. Ribavirin • Synthetic nucleoside • Interferes with viral RNA transcription • Acts on RNA viruses • RSV, HCV • Measles • Lassa fever • Hantaviruses

  23. Ribavirin uses • Ribavirin + alpha-interferon for • Chronic HCV • Monitor Hb + WCC • Aerosol route for RSV, infants • IV for lassa/hanta

  24. Ribavirin toxicities • Potentially teratogenic • C.I. For 6 months pre-pregnancy • Anaemia • Exacerbation of COPD via aerosol

  25. Interferons • Natural glycopeptides • Induced by viruses (dsRNA) • Affect • Antiviral • Antitumour • Immunomodulators • Action, induce cellular enzymes to stop protein synthesis and activate RNA degradation

  26. Interferons, types • Alpha-interferon, B-lymphocytes • Beta-interferon, fibroblasts • Gamma-interferon, T-lymphocytes • Recombinant • Interferon alfacon-1 • Interferon alfacon-2

  27. Interferons, uses • Routes, SC, IM, intralesional • Chronic HCV • Condyloma acuminata-intralesional • Chronic HBV, remission

  28. Interferons, toxicities • Flu-like symptoms • Alopecia • Exac. Psoriasis • Depression • Retinal haemorrhages, rare

  29. Viral hepatitis • HAV, • Supportive • Prophylaxis with HAV IGg • Vaccine • HBV • Interferon-alpha • Lamivudine • Vaccine /HBIG • HCV • Interferon +ribavirin, Tx.

  30. New agents • Oseltramavir – PO • Zanamivir – topical • Neuraminidase inhibitors • Active v Influenza A+B • Sorivudine-VZV+HSV1, 2 step activation • Cidofovir, resistant HSV and CMV

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