Antivirals

Question 1

Aciclovir

Answer 1

• Purine analogue
• activated by thymidine kinase (TK; viral enzyme)
• competed with GTP → inhibits viral DNA polymerase → terminates DNA chain
• narrow spectrum: HSV, VZV

Selectivity – becomes concentrated in infected cells & is only activated in infective cells-↑ affinity for viral DNA polymerase over cellular enzymes

Resistance

• TK^– variants – absence of TK – exist pre-treatment and are selected for, but are non-pathogenic
• TK mutants – altered TK – do appear in therapy but show attenuated virulence (are less harmful)
• Altered DNA polymerase – fully virulent & a real clinical problem

Genital herpes HSV prophylaxis

Question 2

Ganciclovir

Answer 2

• anti-CMV
• acyclic guanosine analogue
• requires phosphorylation (by UL97) → Ganciclovir triphosphate = DNA pol inhibitor
• active against all herpes viruses
• poor oral absorption (valganciclovir)
• toxic (bone marrow)

Question 3

Cidofovir

Answer 3

• anti-CMV
• acyclic phosphonate nucleotide analogue
• non-viral dependant phosphorylation
• inhibits viral DNA polymerase
• broader spectrum (all DNA viruses)
• given via IV infusion
• nephrotoxic

Question 4

Foscarnet

Answer 4

• anti-CMV
• pyrophosphate analogue
• viral DNA polymerase inhibitor
• poor oral absorption
• nephrotoxic

Question 5

Ribavirin

Answer 5

• ? interferes w/ mRNA processing / ? acts as mutagen
• broad spectrum (incl both DNA & RNA viruses)
• clinically disappointing except: severe RSV (give by inhalation); Lassa fever; chronic HCV (w/ IFN)

Question 6

Amantidine

Answer 6

• inhibits uncoating of influenza A
• effective but poorly tolerated due to CNS stimulation, & resistance emerges rapidly
• no longer recommended

Question 7

Neuraminidase inhibitors

Answer 7

• Zanamavir (inhaled)
• Oseltamivir (Tamiflu; oral delivery)
• work against all known influenza NA
• licenced for use in severe infection/high risk patients

H5N1 flu now shows some resistance