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 Activated by virus encoded enzymes Dose related toxicity

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

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

Acyclovir, uses In-vitro –HSV –VZV –EBV –CMV In-vivo –HSV –VZV

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Rimantadine Structural analogue of amantadine Fewer CNS S/E

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

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

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

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

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

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

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

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

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