Resistance Mutations

Question 1

M184v

Answer 1

Phenotypic resistance to 3TC
Reduces viral fitness
Maintains virological activity despite loss of phenotypic activity
Increased susceptibility to TDF, AZT, D4T

Question 2

How do we know increased susceptibility to TDF with m184V?

Answer 2

Nadia study
Switch for patients failing to tdf or AZT + 3TC plus dtg or drv/r
Better results if m184v present

Question 3

Does m184v matter in choice of therapy?

Answer 3

First line - 3Dr no, 2dr don’t know
2nd line - advantageous to maintain 3TC in presence of m184v with PI or DTG (dawning,Nadia)
Suppressed switch - 3Dr no evidence it matters, 2dr no rct evidence to support. Rwd reassuring.

Question 4

What drugs are affected by M184V/I?

Answer 4

3TC, FTC - >200 fold reduction in susceptibility
ABC - 3 fold reduction in susceptibility

Question 5

What does m184v increase susceptibility to?

Answer 5

AZT, tenofovir

Question 6

How do M184I and V relate to each other?

Answer 6

M184I usually emerges first as results from a more common nucleoside substitution but m184v outcompetes within several weeks of viral replication

Question 7

What drugs select k65R?

Answer 7

TDF/TAF, ABC and rarely 3TC
Reduces TF /ABC susceptibility by two fold
3TC/FTC reduced by 5-10 fold

Question 8

What does K65R increase susceptibility to?

Answer 8

AZT

Question 9

What subtype is K65R more likely to occur in?

Answer 9

Subtype C
However no evidence that those with subtype C are at higher risk of VF on a TDF containing regime

Question 10

What are TAMs?

Answer 10

Non polymorphic mutations selected by AZT and d4T.
Near uniform development of m184v during most VF blunts effects of TAMS on AZT/TDF susceptibility but associated with further reductions in ABC susceptibility

Question 11

V90I

Answer 11

Selected in vitro by EFV, ETR, RPV - alone causes little if any reduction in susceptibility

Question 12

K103N

Answer 12

Selected in persons receiving NVP, EFV
Reduces susceptibility 50 and 20 fold respectively

Question 13

K101E/P

Answer 13

Both reduce susceptibility to all NNRTIs bar DOR.

P reduces by >20 fold alone
E - 3-10 fold NVP, 2 fold EFV, ETR. RVP - usually occurs in combination with other resistance mutations

Question 14

L100I

Answer 14

EFV, ETR, RPV
Rarely occurs in isolation
With K103N >5o fold reduced susceptibility to NVP and EFV , 10 fold reduction RPV, 5-10 fold ETR, EFV, DOR

Question 15

Y188L/C/H

Answer 15

Y188L - >50 fold reduced susceptibility to NVP, EFV, DOR

Question 16

G190S

Answer 16

> 50 fold decreased susceptibility to NVP and EFV

Most common NNRTI mutation in A6 viruses from Soviet Union countries as only requires a single g to a mutation to develop

Question 17

V106

Answer 17

NVP, EFV, DOR

greater reduction in susceptibility to NVP than EFV and DOR least effect

V106a in combination with other DOR DRMs can reduce susceptibility to DOR 100fold

Question 18

E138K

Answer 18

RPV, ETR

In combo with m184 or k101e can cause VF on RPV containing regime

Question 19

Y181

Answer 19

C - NNRTIs except doravirine

IV can also variably reduce susceptibility to doravirine

Question 20

Y188

Answer 20

L - reduced susceptibility to NVP, EFV, RPV, DOR

C - NVP only

Question 21

M230L

Answer 21

Up to 5 fold decrease susceptibility for ETR and RPV

> 10 fold for NVP, EFV and DOR

Question 22

G188R

Answer 22

All INSTI drugs

Reported in a significant proportion of persons with VF on people receiving DTG containing regime

Question 23

N155H

Answer 23

Reported in a high proportion of patients developing VF and HIVDR on RAL, EVG, DTG and CAB containing regimes

Question 24

L74

Answer 24

M - prevalence of 1-5% among insti naive pts. Selected by each insti. Alone ok but if combined with other INSTI mutations significantly reduces susceptibility

I - doesn’t reduce susceptibility

Question 25

G140S/A/C

Answer 25

Alone 5 fold reduced EVG susceptibility

In combo with Q148>100fold reducted susceptibility toRAL and EVG (and less so to ral, bic, dtg)

Question 26

Q148H/K/R

Answer 26

Most common INSTI associated DRM in persons with VF on CAB/RPV

Question 27

Why is the genetic barrier to PI resistance high?

Answer 27

Protease mutations reduce PI binding affinity - most binding site mutations require one or more additional mutations to compensate for their reduced fitness

Mutations only develop in viruses exposed to a narrow window of suboptimal drug concentrations that exert selective pressure while allowing virus replication

Question 28

L10F

Answer 28

(And I/V/R/Y)

F- In combination with other mutations
May be associated with reduced virological response to LPV and DOR

I/V - reduce susceptibility or increase replication of viruses containing PI resistance mutations

Question 29

L90M

Answer 29

Reduced susceptibility to ATV and LPV

Question 30

Is there a resistance test for fostamavir?

Answer 30

No

Question 31

Most common RAL resistance pathway?

Answer 31

Q148hrk +/- g140sa
If combined very very high resistance

Question 32

Most common dolutegravir resistance pathway?

Answer 32

R263k

Question 33

Darunavir resistance

Answer 33

POWER 1 and 2 studies
Number of mutations predict likelihood to suppress

If any DRV resistance need to double dose