Resistance mutations

Question 1

M184V

Answer 1

• 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

Question 2

Most common pattern of NRTI mutations in patients experiencing virological failure on tenofovir and NNRTI based first line treatment

Answer 2

M184V/I alone or M184V/I plus K65R

Question 3

K65R

Answer 3

• 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

Question 4

L74V

Answer 4

• Intermediate resistance to ABC
• More common with M184V and in those with ABC/3TC backbone

Question 5

Effect of M184V plus TAMS

Answer 5

• Decreases the impact of TAMs on D4T, TFV and AZT
• Enhances the impact of TAMs on ABC and DDI

Question 6

Classic TAMs (selected by thymidine analogs zidovudine- AZT and stavudine-d4T)

Answer 6

TAM 1 pattern:
M41L
L210W
T215Y

TAM 2 pattern:
D67N
K70R
T215Y/F
K219Q/E

Question 7

Presence of 3 or more TAMs or K65R

Answer 7

• Reduced susceptibility to 3TC/FTC
• Type 1 TAMS have greater negative impact on virological response to ABC or TDF than type 2 TAMS

Question 8

Primary NNRTI resistance mutations:

Answer 8

• 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

Question 9

What INSTI resistance might you see in those with Vf on DTG?

Answer 9

• G118R and R263K, associated with 5-10 fold reduced susceptibility to most INSTIs

Question 10

Most common INSTI mutation seen in persons with virological failure receiving CAB/RPV

Answer 10

Q148HR

Question 11

G140S/A/C together with Q148H/R/K

Answer 11

Together >100 reduced susceptibility to RAL and EVG, 10 fold CAB, 2-5 fold DTG + BIC

Question 12

E92Q/G/V

Answer 12

Reduces RAL 5 fold and EVG 30 fold, does not reduce BIC/CAB/DTG

Question 13

Y143C/R

Answer 13

Selected by RAL and causes reduced RAL susceptibility especially if in combination with T97A

Question 14

K103N

Answer 14

• Most commonly transmitted drug resistance mutation
• Selected in persons on NVP or EFV (and reduces susceptibility to)

Question 15

E138K

Answer 15

• 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)

Question 16

3 Common RAL resistance mutations:

Answer 16

• 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)

Question 17

Failing dolutegravir:

Answer 17

• R263K most common
• N155H seen in a third
• Q1488HRK

Question 18

Darunavir resistance mutations

Answer 18

• Double dose darunavir with any DRV resistance mutation

Question 19

Typical resistance patterns on failing NRTI

Answer 19

70% Wild type
NRTI: M184V (3TC/FTC)

Question 20

Typical resistance pattern failing NNRTI

Answer 20

K103N/Y181C (EFV)
K101/E138K (RPV)

Question 21

Typical resistance pattern failing INSTI

Answer 21

Q148/N155/Y143 (RAL)
R263K (DTG)

Question 22

What constitutes a positive result on western blot?

Answer 22

• Presence of bands at at least 2 of the following:
• p24, gp41 and gp120/160

Question 23

Causes of indeterminate Western blot

Answer 23

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

Question 24

Definition of sensitivity

Answer 24

Proportion of true positives that will correctly be identified as positive

Question 25

Definition of specificity

Answer 25

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)