Antiviral resistance

Question 1

What is the mechanism of action of aciclovir?

Answer 1

guanosine analogue

requires phosphorylation by thymidine kinase

inhibits DNA polymeraseby acting as a nucleotide, and causing chain termination

Question 2

What are main resistance mutations to aciclovir?

Answer 2

Common - Thymidine kinase mutations - UL23

Rarer - DNA polymerase mutations - UL30

Question 3

What is the mechanism of action of foscarnet?

Answer 3

non-competitive DNA polymerase inhibitor

blocks pyrophosphate binding site, preventing cleavage of pyrophosphate from deoxynucleotide triphsophates - inhibiting DNA polymerase

Question 4

What are main resistance mutations to foscarnet?

Answer 4

DNA polymerase mutations - UL54

some mutations can result in cross-resistance to aciclovir, but this is rare

Question 5

What are main mechanism of action of cidofovir?

Answer 5

cytosine analogue

does not require phosphorylation (as compared to aciclovir)

Question 6

What are main resistance mutations to cidofovir?

Answer 6

DNA polymerase mutations - UL54

cidofovir can overcome UL23 mutations commonly seen in aciclovir resistance

Question 7

What are main mechanism of action of ganciclovir?

Answer 7

guanosine analogue

requires phosphorylation by thymidine kinase

inhibits DNA polymerase

Question 8

What are main resistance mutations to ganciclovir?

Answer 8

majority viral phosphotransferase mutations - UL97

minority - DNA polymerase mutations - UL54. This mutation also confers cross-resistance to cidofovir

Question 9

What is the mechanism of action of lamivudine?

Answer 9

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

Question 10

What are main resistance mutations to lamivudine?

Answer 10

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

Question 11

What is the mechanism of action of entecavir?

Answer 11

nucleoside analogue

1 - competitively inhibit Reverse Transcriptase
2 - incorporated into viral DNA acting as a chain terminator

Question 12

What are main resistance mutations to entecavir?

Answer 12

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

Question 13

What is the mechanism of action of tenofovir?

Answer 13

nucleoside analogue

1 - competitively inhibit Reverse Transcriptase
2 - incorporated into viral DNA acting as a chain terminator

Question 14

What are main resistance mutations to tenofovir?

Answer 14

No resistance mutation identified

Less effective in those who are resistant to Adefovir

Question 15

Patient with lamivudine resistance

What drug to switch them to?

Answer 15

Lamivudine switch to tenofovir

Question 16

Patient with entecavir resistance

What drug to switch them to?

Answer 16

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

Question 17

Patient with tenofovir resistance

What drug to switch them to?

Answer 17

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

Question 18

What new HBV drugs are in development?

Answer 18

HBV entry inhibitors

siRNA against viral transcripts

inhibitors of viral capsid formation

drugs targeting cccDNA

all studies in early trials

Question 19

What is oseltamivir mechanism of action?

Answer 19

inhibits viral neuraminidase on surface of virus, preventing budding from host cell

Question 20

What is mechanism of resistance to oseltamivir?

Answer 20

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

Question 21

What is zanamavir mechanism of action?

Answer 21

inhibits viral neuraminidase on surface of virus, preventing budding from host cell

Question 22

What is mechanism of resistance to zanamavir?

Answer 22

resistance very rare

mutations occur in neuraminidase enzyme

I223R - cross-resistance with oseltamivir

Q136K - only resistance to zanamivir

Question 23

What is ribavirin mechanism of action?

Answer 23

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

Question 24

What is mechanism of resistance to ribavirin?

Answer 24

resistance rare

Question 25

Review drug resistance word summary

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