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