Antiviral resistance Flashcards
What is the mechanism of action of aciclovir?
guanosine analogue
requires phosphorylation by thymidine kinase
inhibits DNA polymeraseby acting as a nucleotide, and causing chain termination
What are main resistance mutations to aciclovir?
Common - Thymidine kinase mutations - UL23
Rarer - DNA polymerase mutations - UL30
What is the mechanism of action of foscarnet?
non-competitive DNA polymerase inhibitor
blocks pyrophosphate binding site, preventing cleavage of pyrophosphate from deoxynucleotide triphsophates - inhibiting DNA polymerase
What are main resistance mutations to foscarnet?
DNA polymerase mutations - UL54
some mutations can result in cross-resistance to aciclovir, but this is rare
What are main mechanism of action of cidofovir?
cytosine analogue
does not require phosphorylation (as compared to aciclovir)
What are main resistance mutations to cidofovir?
DNA polymerase mutations - UL54
cidofovir can overcome UL23 mutations commonly seen in aciclovir resistance
What are main mechanism of action of ganciclovir?
guanosine analogue
requires phosphorylation by thymidine kinase
inhibits DNA polymerase
What are main resistance mutations to ganciclovir?
majority viral phosphotransferase mutations - UL97
minority - DNA polymerase mutations - UL54. This mutation also confers cross-resistance to cidofovir
What is the mechanism of action of lamivudine?
nucleoside analogue of cytidine - phosphorylated to its active form
1 - competitively inhibit Reverse Transcriptase
2 - incorporated into viral DNA acting as a chain terminator
reverse transcriptase inhibitor of HIV/ HBV
What are main resistance mutations to lamivudine?
mutations in highly conserved YMDD locus of HBV-RNA-dependent DNA polymerase
Most common YMDD mutation - M204V/I
Has a fitness cost, but other mutations may bring activity levels back to normal level
resistance occurs in 38% at 2 years, 67% at 4 years
YMDD = tyrosine-methionine-aspartate-aspartate
M204V/I - HBV DNA polymerase resistance
M184V - HIV RT resistance
What is the mechanism of action of entecavir?
nucleoside analogue
1 - competitively inhibit Reverse Transcriptase
2 - incorporated into viral DNA acting as a chain terminator
What are main resistance mutations to entecavir?
Entecavir has a much higher barrier to resistance than lamivudine - 1% resistance rate.
Entecavir resistance normally only occurs after failure on lamivudine, in which resistance has already been pre-selected - 50% resistance rate
mutations in highly conserved YMDD locus of HBV-RNA-dependent DNA polymerase
Most commonly patient has YMDD mutation -
- M204V/I from lamivudine failure
Then develop following ETV signature mutation in the “B domain”:
- I169T + M250V
- T184G + S2021/G
What is the mechanism of action of tenofovir?
nucleoside analogue
1 - competitively inhibit Reverse Transcriptase
2 - incorporated into viral DNA acting as a chain terminator
What are main resistance mutations to tenofovir?
No resistance mutation identified
Less effective in those who are resistant to Adefovir
Patient with lamivudine resistance
What drug to switch them to?
Lamivudine switch to tenofovir
Patient with entecavir resistance
What drug to switch them to?
Entecavir switch to tenofovir
or add tenofovir in combination therapy
Switching to tenofovir is safe as no cross-resistance is expected from entecavir mutations
A randomized study including 90 patients with ETV resistance suggested that both strategies (TDF alone vs. ETV-TDF combination) are similarly effective in suppression of viral replication (28). However, both highly effective drugs can be safely combined and represent an efficient rescue in patients with complex resistance patterns
Patient with tenofovir resistance
What drug to switch them to?
Tenofovir switch to entecavir
or add entecavir in combination therapy
Tenofovir resistance not expected, but sometimes it is no as effective as expected. Switching to entecavir should not provide any risk of cross-resistance
What new HBV drugs are in development?
HBV entry inhibitors
siRNA against viral transcripts
inhibitors of viral capsid formation
drugs targeting cccDNA
all studies in early trials
What is oseltamivir mechanism of action?
inhibits viral neuraminidase on surface of virus, preventing budding from host cell
What is mechanism of resistance to oseltamivir?
majority point mutation H274/275Y in neuraminidase enzyme
influenza A N1 viruses most likely to have this
Influenza B or A H3N2 lower risk of resistance
rarely I223R which gives resistance to zanamivir
What is zanamavir mechanism of action?
inhibits viral neuraminidase on surface of virus, preventing budding from host cell
What is mechanism of resistance to zanamavir?
resistance very rare
mutations occur in neuraminidase enzyme
I223R - cross-resistance with oseltamivir
Q136K - only resistance to zanamivir
What is ribavirin mechanism of action?
multiple actions
- directly inhibits viral mRNA polymerase by binding to it
- guanosine analogue - limits viral RNA synthesis
- increases viral mutation, leading to defective replication
- upregulates Th1 response - interferon production increased
What is mechanism of resistance to ribavirin?
resistance rare
Review drug resistance word summary
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