Resistance Mutations Flashcards

1
Q

M184v

A

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

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2
Q

How do we know increased susceptibility to TDF with m184V?

A

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

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3
Q

Does m184v matter in choice of therapy?

A

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.

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4
Q

What drugs are affected by M184V/I?

A

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

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5
Q

What does m184v increase susceptibility to?

A

AZT, tenofovir

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6
Q

How do M184I and V relate to each other?

A

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

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7
Q

What drugs select k65R?

A

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

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8
Q

What does K65R increase susceptibility to?

A

AZT

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9
Q

What subtype is K65R more likely to occur in?

A

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

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10
Q

What are TAMs?

A

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

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11
Q

V90I

A

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

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12
Q

K103N

A

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

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13
Q

K101E/P

A

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

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14
Q

L100I

A

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

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15
Q

Y188L/C/H

A

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

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16
Q

G190S

A

> 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

17
Q

V106

A

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

18
Q

E138K

A

RPV, ETR

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

19
Q

Y181

A

C - NNRTIs except doravirine

IV can also variably reduce susceptibility to doravirine

20
Q

Y188

A

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

C - NVP only

21
Q

M230L

A

Up to 5 fold decrease susceptibility for ETR and RPV

> 10 fold for NVP, EFV and DOR

22
Q

G188R

A

All INSTI drugs

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

23
Q

N155H

A

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

24
Q

L74

A

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

25
Q

G140S/A/C

A

Alone 5 fold reduced EVG susceptibility

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

26
Q

Q148H/K/R

A

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

27
Q

Why is the genetic barrier to PI resistance high?

A

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

28
Q

L10F

A

(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

29
Q

L90M

A

Reduced susceptibility to ATV and LPV

30
Q

Is there a resistance test for fostamavir?

A

No

31
Q

Most common RAL resistance pathway?

A

Q148hrk +/- g140sa
If combined very very high resistance

32
Q

Most common dolutegravir resistance pathway?

A

R263k

33
Q

Darunavir resistance

A

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

If any DRV resistance need to double dose