Resistance Mutations Flashcards
M184v
Phenotypic resistance to 3TC
Reduces viral fitness
Maintains virological activity despite loss of phenotypic activity
Increased susceptibility to TDF, AZT, D4T
How do we know increased susceptibility to TDF with m184V?
Nadia study
Switch for patients failing to tdf or AZT + 3TC plus dtg or drv/r
Better results if m184v present
Does m184v matter in choice of therapy?
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.
What drugs are affected by M184V/I?
3TC, FTC - >200 fold reduction in susceptibility
ABC - 3 fold reduction in susceptibility
What does m184v increase susceptibility to?
AZT, tenofovir
How do M184I and V relate to each other?
M184I usually emerges first as results from a more common nucleoside substitution but m184v outcompetes within several weeks of viral replication
What drugs select k65R?
TDF/TAF, ABC and rarely 3TC
Reduces TF /ABC susceptibility by two fold
3TC/FTC reduced by 5-10 fold
What does K65R increase susceptibility to?
AZT
What subtype is K65R more likely to occur in?
Subtype C
However no evidence that those with subtype C are at higher risk of VF on a TDF containing regime
What are TAMs?
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
V90I
Selected in vitro by EFV, ETR, RPV - alone causes little if any reduction in susceptibility
K103N
Selected in persons receiving NVP, EFV
Reduces susceptibility 50 and 20 fold respectively
K101E/P
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
L100I
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
Y188L/C/H
Y188L - >50 fold reduced susceptibility to NVP, EFV, DOR
G190S
> 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
V106
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
E138K
RPV, ETR
In combo with m184 or k101e can cause VF on RPV containing regime
Y181
C - NNRTIs except doravirine
IV can also variably reduce susceptibility to doravirine
Y188
L - reduced susceptibility to NVP, EFV, RPV, DOR
C - NVP only
M230L
Up to 5 fold decrease susceptibility for ETR and RPV
> 10 fold for NVP, EFV and DOR
G188R
All INSTI drugs
Reported in a significant proportion of persons with VF on people receiving DTG containing regime
N155H
Reported in a high proportion of patients developing VF and HIVDR on RAL, EVG, DTG and CAB containing regimes
L74
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
G140S/A/C
Alone 5 fold reduced EVG susceptibility
In combo with Q148>100fold reducted susceptibility toRAL and EVG (and less so to ral, bic, dtg)
Q148H/K/R
Most common INSTI associated DRM in persons with VF on CAB/RPV
Why is the genetic barrier to PI resistance high?
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
L10F
(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
L90M
Reduced susceptibility to ATV and LPV
Is there a resistance test for fostamavir?
No
Most common RAL resistance pathway?
Q148hrk +/- g140sa
If combined very very high resistance
Most common dolutegravir resistance pathway?
R263k
Darunavir resistance
POWER 1 and 2 studies
Number of mutations predict likelihood to suppress
If any DRV resistance need to double dose
