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