Resistance mutations Flashcards
M184V
- Most commonly occurring NRTI resistance mutations
- High level (reduces susceptibility 200 fold) to lamivudine and emtricitabine
- Low level resistance to abacavir however if also K65R or L74V then high level resistance
- Associated with reduced virus replication
- Found in up to 1% new diagnosed persons
Most common pattern of NRTI mutations in patients experiencing virological failure on tenofovir and NNRTI based first line treatment
M184V/I alone or M184V/I plus K65R
K65R
- NRTI resistance, intermediate resistance TDF, FTC, ABC, 3TC and increased susceptibility to AZT
- (However NADIA trial showed TDF/3TC still as effective as AZT/3TC even in presence of K65R)
- With M184V also high level resistance to ABC
- More common in Clade C
L74V
- Intermediate resistance to ABC
- More common with M184V and in those with ABC/3TC backbone
Effect of M184V plus TAMS
- Decreases the impact of TAMs on D4T, TFV and AZT
- Enhances the impact of TAMs on ABC and DDI
Classic TAMs (selected by thymidine analogs zidovudine- AZT and stavudine-d4T)
TAM 1 pattern:
M41L
L210W
T215Y
TAM 2 pattern:
D67N
K70R
T215Y/F
K219Q/E
Presence of 3 or more TAMs or K65R
- Reduced susceptibility to 3TC/FTC
- Type 1 TAMS have greater negative impact on virological response to ABC or TDF than type 2 TAMS
Primary NNRTI resistance mutations:
- K101, K103N/S, Y181C/I/V, V106A/M, Y188L/C/H, G190A/S/E, E138K
-> Cause high level resistance to NVP, variable resistance to EFZ - K103N: most commonly transmitted drug resistance mutation
What INSTI resistance might you see in those with Vf on DTG?
- G118R and R263K, associated with 5-10 fold reduced susceptibility to most INSTIs
Most common INSTI mutation seen in persons with virological failure receiving CAB/RPV
Q148HR
G140S/A/C together with Q148H/R/K
Together >100 reduced susceptibility to RAL and EVG, 10 fold CAB, 2-5 fold DTG + BIC
E92Q/G/V
Reduces RAL 5 fold and EVG 30 fold, does not reduce BIC/CAB/DTG
Y143C/R
Selected by RAL and causes reduced RAL susceptibility especially if in combination with T97A
K103N
- Most commonly transmitted drug resistance mutation
- Selected in persons on NVP or EFV (and reduces susceptibility to)
E138K
- Selected in a high proportion of people failing RPV, and smaller proportion receiving ETV, but does not appear to reduce susceptibility to EFV, DOR or NVP
- (often develops with a M184V when failing something with RPV)
3 Common RAL resistance mutations:
- Q148HRK (also most common seen in VF in CAB/RPV)
- N155H (selected by RAL/EVG/DTG/CAB, reduces susceptibility to RAL/EVG with minimal effect on others)
- Y143CR (especially when in combination with T97A)
Failing dolutegravir:
- R263K most common
- N155H seen in a third
- Q1488HRK
Darunavir resistance mutations
- Double dose darunavir with any DRV resistance mutation
Typical resistance patterns on failing NRTI
70% Wild type
NRTI: M184V (3TC/FTC)
Typical resistance pattern failing NNRTI
K103N/Y181C (EFV)
K101/E138K (RPV)
Typical resistance pattern failing INSTI
Q148/N155/Y143 (RAL)
R263K (DTG)
What constitutes a positive result on western blot?
- Presence of bands at at least 2 of the following:
- p24, gp41 and gp120/160
Causes of indeterminate Western blot
o Indeterminate:
Presence of some bands but not meeting criteria
Can occur in early HIV infection, HIV-2, pregnancy or cross reactivity with other antibodies e.g. recent Flu vaccine or autoimmune disorder
Definition of sensitivity
Proportion of true positives that will correctly be identified as positive
Definition of specificity
Proportion of true negatives that are correctly identified as negative (i.e. if you test positive, how sure can we be they don’t have it)
