HIV drug resistance

Question 1

HIV has high rate of replication - 10^9 virion produced per day
RT is also error prone - low fidelity

Which drugs have a low barrier to resistance?

Answer 1

Single mutation can confer resistance

3TC - Lamivudine
EFV - Efavirenz
NVP - Nevirapine

Question 2

Which drugs have high barrier to resistance?

Answer 2

Require multiple mutations for resistance

Protease inhibitors

Question 3

When is the best time to test for drug resistance?

Answer 3

at diagnosis - see if they have acquired a mutant virus

on treatment - need drug pressure to increase proportion of resistant strains

Question 4

What are benefits of genotypic resistance testing?

Answer 4

detects mutations directly

cheap

quick

Question 5

What are drawbacks of genotypic resistance testing?

Answer 5

only identifies known mutations

difficult to interpret results if multiple mutations present

genotypic analysis does not always match phenotypic analysis. Can compare genotypes to known database of genotype-phenotype matches, to estimate probability

Question 6

What are benefits of phenotypic resistance testing?

Answer 6

can directly see whether there is cytopathic effect and whether drug is effective

can also measure degree of resistance - from full to partial resistance

Question 7

What are drawbacks of phenotypic resistance testing?

Answer 7

expensive

takes long time

low sensitivity to minority strains of virus

Question 8

What is a signature mutation?

What is an accessory mutation?

Answer 8

signature mutation - typically associated with resistance to one particular drug. Will have to switch drugs

accessory mutation - increase viral fitness, which may be a marker that full resistance will soon occur. Recommend switching drugs

Question 9

NRTIs

Thymidine analogues
- zidovudine
- stavudine

What mutations are common?
TAMS

Answer 9

Thymidine analogue mutations (TAMs)

TAM1 - L210W+ M41L + T215Y

TAM 2 - D67N + K70R + K219Q/E/N

need to accumulate few mutations, and then have cross resistance to all NRTIs

Called TAMs as first reported about patient on zidovudine

Question 10

NRTIs

Cytidine analogues
- lamivudine
- emtricitabine

What mutations are common?

Answer 10

Low genetic barrier to resistance

M184V mutation - most common resistance to lamivudine/ emtricitabine

Lamivudine
M204V/I - HBV DNA polymerase resistance
M184V - HIV RT resistance

Question 11

NRTIs

Tenofovir

What mutations are common?

Answer 11

K65R mutation

Also confers resistance to abacavir

Question 12

NRTIs

abacavir
didanosine

What mutations are common?

Answer 12

L74V

Question 13

What does the mutation notation mean?

e.g K65R

Answer 13

K - amino acid wild-type. K is abbreviation of Lysine

65 - amino acid position

R - amino acid substitution conferring resistance. R is abbreviation or arginine

Question 14

NNRTIs

Efavirenz
Nevirapine

What mutations are common?

Answer 14

low genetic barrier

K103N
Y181C

cross-resistance to multiple drugs

Question 15

PIs

What mutations are common?

Answer 15

High barrier to resistance, especially when boosted

Question 16

Fusion inhibitors

enfuvirtide
maraviroc

What mutations are common?

Answer 16

enfuvirtide - gp41 envelope gene mutation - low barrier

maraviroc - check tropism R5 virus before treatment. Resistance can arise due to tropism switch or mutations

Question 17

Integrase inhibitors

Raltegravir
Elvitegraivr
Dolutegravir

What mutations are common?

Answer 17

Raltegravir/ Elvitegravir - Q148 H/K/R
When they fail, need to switch treatment, as could accrue more mutations that result in dolutegravir resistance

Dolutegravir - can work against 148 mutants, though needs high doses

Question 18

Patient with HIV and cardiac stents

What drugs should be avoided?

Answer 18

ritonavir can reduce clopidogrel levels

ritonavir can increase ticagrelor levels