David Spach MD Principal Investigator NW AETC Professor of Medicine Division of Infectious Diseases University of Washington Last Updated June 8 2015 NRTI Resistance Outline Mechanism of NRTI Resistance ID: 586630
Download Presentation The PPT/PDF document "Management of NRTI Resistance" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Management of NRTI Resistance
David Spach, MDPrincipal Investigator, NW AETCProfessor of Medicine, Division of Infectious DiseasesUniversity of Washington
Last Updated: June 8, 2015Slide2
NRTI Resistance: Outline
Mechanism of NRTI Resistance
M184V Mutation
K65R Mutation
Thymidine Analog
M
utations (TAMs)Slide3
Mechanisms of NRTI Resistance
Resistance to Nucleoside Reverse Transcriptase InhibitorsSlide4
HIV Reverse Transcription
Conversion of HIV RNA to HIV DNA
HIV DNA
HIV RNA
Reverse Transcription
Reverse
TranscriptaseSlide5
HIV Reverse Transcription
HIV DNA
HIV RNA
Reverse TranscriptaseSlide6
HIV Reverse Transcription
HIV DNA
HIV RNA
Reverse Transcriptase
Nucleotides (human)Slide7
HIV Reverse Transcription
HIV DNA
HIV RNA
Reverse Transcriptase
Nucleotides (human)
Template
PrimerSlide8
Inhibition of HIV Reverse Transcription
NRTI Mechanism of Action
HIV DNA
HIV RNA
NRTI
Nucleotides
Reverse Transcriptase
(1) Incorporation of NRTI
(2) Primer Blocking
Template
PrimerSlide9
Inhibition of HIV Reverse Transcription
NRTI Mechanism of Action
HIV DNA
HIV RNA
NRTI
Nucleotides
Reverse Transcriptase
Chain TerminationSlide10
Nucleoside Reverse Transcriptase Inhibitors (
NRTIs)
Biochemical Mechanisms of Resistance
1. Discrimination Pathway
Decreased incorporation of NRTIs
Process favors authentic nucleotides over NRTIs
2. Nucleotide Excision PathwayEnhanced removal of incorporated NRTI
Results from phosphorolytic reaction that leads to primer unblockingFrom: Shafer RW, Schapiro JW. AIDS Rev. 2008;10:67-
84.Slide11
Biochemical Mechanisms of NRTI Resistance
(1) Discrimination Pathway
HIV DNA
HIV RNA
Decreased Incorporation of NRTI
NRTI
Nucleotides
Enhanced discrimination against NRTIs and decreased incorporation of NRTIs in favor of host nucleotides
Enhanced Incorporation of Host
Nucleotides
Reverse TranscriptaseSlide12
Biochemical Mechanisms of NRTI Resistance
(2) Excision Pathway
HIV DNA
HIV RNA
Excision (Primer Unblocking)
NRTI
Nucleotides
Excision
of incorporated NRTI by promoting
pyrophosphorolysis
(primer unblocking)
Reverse TranscriptaseSlide13
Common NRTI Resistance Mutations
Resistance to Nucleoside Reverse Transcriptase InhibitorsSlide14
Wild Type HIV-1: NRTIs
Lamivudine
Emtricitabine
Didanosine
Abacavir
Zidovudine
Stavudine
Tenofovir
Wild Type HIV
High-Level Resistance
Low-Level Resistance
Increased
SusceptibilitySlide15
Case History
A 33-year-old woman develops virologic failure while taking tenofovir-emtricitabine-efavirenz (
Atripla). Recent HIV RNA levels were 468 copies/ml and 1482 copies/ml. A baseline genotype showed no
mutations, but genotype ordered after virologic failure shows M184V and K103N mutations.
In constructing a new antiretroviral regimen, is there value in maintaining the M184V mutation?Slide16
Source: Gupta R, et al.
Clin Infect Dis. 2008;47:712-22.
M184V Mutation Frequently Emerges with Virologic Failure
Initial PI-Based and NNRTI-Based Regimens
NNRTI
-Based
Studies: Study 903, Study 934, COMBINE
PI-Based
Studies
ACTG 5142, Study 089, MONARK, Study 863, ESS4001Slide17
Source:
Eron JJ, et al. N Engl J Med 1995;333:1662-9.Response to Lamivudine Monotherapy
HIV RNA Levels Before and After M184V Mutation
Treatment time (weeks)
-2.0
0.0
-0.5
-1.0
-1.5
0.5
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Lamivudine
300 mg BID only
Lamivudine Resistance
(M184
V
)
Change in HIV RNA (Log
10
)Slide18
M184V/I Mutation
Lamivudine
Emtricitabine
Didanosine
Abacavir
Zidovudine
Stavudine
Tenofovir
M184V/I Mutation
High-Level Resistance
Low-Level Resistance
Increased
SusceptibilitySlide19
Source: Stanford University: HIV Drug Resistance Database
(accessed 6/9/2015)M184V/I Mutation Score
Mutation Scoring: Stanford HIV Drug Resistance Database
RT
3TC
ABC
AZT
D4T
DDI
FTC
TDF
M184V/I
60
15
-10
-10
10
60
-10
Total
60
15
-10
-10
10
60
-10Slide20
Source:
Castagna
A, et al. AIDS. 2006;20:795-803.
Lamivudine Monotherapy versus Treatment Interruption in Patients with M184V Mutation
All ARV Meds Discontinued
n = 29Lamivudine 300 mg qd
n = 29
Resume Therapy
- CD4 < 350
- CDC B or C Event
Patients on failing therapy requesting treatment interruption
CD4 >
500 cells/mm3
HIV RNA > 1,000 copies/ml
M184V Mutationn = 58Slide21
Source:
Castagna A, et al. AIDS. 2006;20:795-803.Lamivudine Monotherapy versus Treatment Interruption in Patients with M184V Mutation
Parameter at Week 48
Lamivudine Continued
All ARVs Stopped
Change in CD4 Cell Count
-141
-215
Change in CD4 Cell %
-3%
-8%*Change in HIV RNA
+0.57 log
+1.11 log**> Grade 3 Adverse Events
7%
31%***
Immunologic/Clinical Failure41%
69%
*P = 0.001; **P = 0.002; ***P < 0.001Slide22
Why Maintain the M184V/I Mutation?
Lamivudine and emtricitabine maintain partial viral activity Increases susceptibility to tenofovir, zidovudine, and stavudine
Slows emergence of resistance to tenofovir, zidovudine, and stavudine
Associated with reduced
virologic fitnessSlide23
Case History
A 49-year-old man presents as a new patient to the clinic after recently moving. He has a long history of taking antiretroviral therapy, beginning in the early 1990s. He has been off antiretroviral therapy for 6 months. The most recent genotype shows the following mutations:
RT: M41L, K103N, Y181C, M184V, L210W, T215YProtease: D30N, I54L, and L90M
What is the significance of the RT mutations
M41L, L210W, and T215?Slide24
Thymidine Analog Mutations (TAMs)
M41
L
D67
NK70RL210
WT215YFK219
QE
Thymidine Analogs
Thymidine Analog Mutations
ZidovudineStavudineSlide25
M184V/I and Multiple TAMs
Lamivudine
Emtricitabine
Didanosine
Abacavir
Zidovudine
Stavudine
Tenofovir
High-Level Resistance
Low-Level Resistance
Increased
Susceptibility
M184V/I + 3TAMs (M41L, L210W, T215Y)Slide26
Source: Stanford University: HIV Drug Resistance Database (accessed 11/18/2014)
M184V/I and Multiple TAMs (M41L, L210W, T215Y
)
Mutation Scoring: Stanford HIV Drug Resistance Database
RT
3TC
ABC
AZT
D4T
DDI
FTC
TDF
M41L
5
10
15
15
10
5
10
M184V
60
15
-10
-10
10
60
-10
L210W
5
10
15
15
10
5
10
T215Y
5
15
45
45
15
5
15
T215Y
+ M41L
–
10
10
10
10
–
10
T210W + T215Y
–
10
10
10
10
–
10
T210W + M41L
–
10
10
10
10
–
10
Total
75
80
95
95
75
75
55Slide27
Thymidine Analog Mutations (TAMs)
M
41
L
L
210W
T
215Y/F
K70R
K
219Q/E
D67N
Thymidine Analog Mutations (TAMs)
Wild Type HIV
Zidovudine or StavudineSlide28
Distinct TAM Pathways to Resistance
Zidovudine or Stavudine
Source: Shafer RW, Schapiro JM. AIDS Rev. 2008;10:67-84.
Type-1 TAM Pattern
Type-2 TAM Pattern
M41
L
L210
W
T215
Y
K70
R
K219
Q
/E
D67
N
T215
FSlide29
Distinct TAM Pathways to Resistance
Zidovudine or Stavudine
Source: Shafer RW, Schapiro JM. AIDS Rev.2008;10:67-84.
Higher level of zidovudine resistance
Higher level NRTI cross-resistance
Less decrease in resistance with M184V
Lower level of zidovudine resistance
Lower level of NRTI cross-resistance
More decrease in resistance with M184V
Type-1 TAM Pattern
Type-2 TAM Pattern
M41
L
L210
W
T215
Y
K70
R
K219
Q
/E
D67
N
T215
FSlide30
Resistance Pathway with Thymidine Analog + Lamivudine
Zidovudine + Lamivudine
or
Stavudine + Lamivudine
Type-1 TAM Pattern
Type-2 TAM Pattern
M41
L
L210
W
T215
Y
K70
R
K219Q/E
D67N
T215
F
M184V/ISlide31
Case History
A 56-year-old man with a history of extensive antiretroviral therapy and resistance presents to discuss a new regimen. His genotype has multiple mutations, including a K65R mutation.
What is the impact of the K65R mutation on drugs in the NRTI class?Slide32
K65R Mutation
Didanosine
Abacavir
Stavudine
Tenofovir
High-Level Resistance
Low-Level Resistance
Increased
Susceptibility
K65R Mutation
Lamivudine
Emtricitabine
ZidovudineSlide33
Source: Stanford University: HIV Drug Resistance Database (accessed 6/
9/2015)K65R Mutation Score
Mutation Scoring: Stanford HIV Drug Resistance Database
RT
3TC
ABC
AZT
D4T
DDI
FTC
TDF
K65R
30
45
-15
45
60
30
60
Total
30
45
-15
45
60
30
60Slide34
Resistance Pathway with Tenofovir + Emtricitabine
M184
V/
I
K65
R
Tenofovir + EmtricitabineSlide35
Resistance Pathway with Abacavir + Lamivudine
M184
V/
I
L74
V
K65
R
Abacavir + LamivudineSlide36
M184V/I
+ K65R Mutations
Lamivudine
Emtricitabine
Didanosine
Abacavir
Zidovudine
Stavudine
Tenofovir
High-Level Resistance
Low-Level Resistance
Increased
Susceptibility
M184V/I + K65R MutationsSlide37
Source: Stanford University: HIV Drug Resistance Database (accessed 11/18/2014)
M184V/I + K65R Mutation Score
Mutation Scoring: Stanford HIV Drug Resistance Database
RT
3TC
ABC
AZT
D4T
DDI
FTC
TDF
K65R
30
45
-15
45
60
30
60
M184V
60
15
-10
-10
10
60
-10
K65R + M184V
–
–
–
10
–
–
10
Total
90
60
-25
45
70
90
60Slide38
NRTI Resistance: Summary
Resistance to Nucleoside Reverse Transcriptase InhibitorsSlide39
NNRTI Resistance: Summary
Two major resistance mechanisms: discrimination and excisionM184V common and reduces emtricitabine/lamivudine activityOnce M184V develops, maintaining mutation has advantagesMultiple TAMs cause broad NRTI resistance
K65R has major impact on NRTIs except for zidovudineIn most NRTI resistance pathways, M184V develops earlySlide40
Questions