Resistance Mechanisms

Question 1

What mutations in HSV causes Aciclovir resistance? 2

Answer 1

UL23 gene (95%)which encodes for viral thymidine kinase enzyme. Mutation in TK enzyme prevents Aciclovir activation via phosphorylation.

UL30 (5%) DNA POL

Question 2

What mutations in influenza cause osteltamavir resistance?

Answer 2

H275Y mutation; a histidine to tyrosine substitution at amino acid 275 of the influenza A N1 neuraminidase

The H275Y mutation reduces the susceptibility (IC50; the half maximal inhibitory concentration) of influenza A H1N1 to oseltamivir by approximately 400-fold but not zanamivir [13, 29]. Peramivir binds to sialic acid residues in a similar manner to oseltamivir and is also affected by the H275Y mutation

Due to certain difference in the neuraminidase enzyme structure, neuraminidase resistance is less likely to occur in influenza A H3N2 and influenza B compared with A H1N1 pdm09 without causing significant loss of neuraminidase enzymatic function and reduced viral fitness

Lampejo, T. Influenza and antiviral resistance: an overview. Eur J Clin Microbiol Infect Dis 39, 1201–1208 (2020). https://doi.org/10.1007/s10096-020-03840-9

Remember H275Y

The swine flu that caused a problem recently was in 75Y old, Was N2 =H275Y

Question 3

To which HCV agents are most clinical significant resistance mutations

Answer 3

NS5A inhibtors

End in tasvir, proteas inhibitors

Velpatasvir
Elbasvir
Pibrentasvir

genotypes 1l, 4r, 3b, 3g, 6u, 6v
among others) harbour natural polymorphisms that confer inherent resistance to NS5A inhibitors

Question 4

Key HCV mutation

Answer 4

Y93H

Looks like YEAH

Question 5

K103N

Answer 5

NNRTI resistance

Question 6

N155N

Answer 6

INSTI resistance

Question 7

E138K mutaion

Answer 7

NNRTI
Induced by rilpivirine.
Other NNRTI mutations include Y181C (neviripine)
K103N (Efavirenz)

Question 8

Absolute worst HBV mutation

Answer 8

A181T/V
- resistance to ADV + I resistance to TDF, and lamvidine

Management:
If LAM naive ->ETV or TDF
If LAM resistance also -> TDF

Question 9

CMV resistance testing

Answer 9

UL97 ganciclovir (and maribavir)
UL54 ganciclovir cidofovir foscarnet
UL56 letermovir

Question 9

Management of HBV resistance

Answer 9

LAM resistance Switch to TDF or TAF
TBV resistance Switch to TDF or TAF
ETV resistance Switch to TDF or TAF
ADV resistance If LAM-naïve: switch to ETV or TDF or TAF
If LAM-resistance: switch to TDF or TAF
If HBV DNA plateaus: add ETV*** or switch to ETV

TDF or TAF resistance** If LAM-naïve: switch to ETV
If LAM-R: add ETV*

Multidrug resistance Switch to ETV plus TDF or TAF combination

Question 10

What is a nonpolymorphic mutation

Answer 10

A nonpolymorphic mutation is one that does not occur in the absence of therapy

non synonymous mutation: change in nucleic acid but doesn’t change amino aci