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Management of NRTI Resistance Management of NRTI Resistance

Management of NRTI Resistance - PowerPoint Presentation

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Management of NRTI Resistance - PPT Presentation

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

hiv resistance mutation m184v resistance hiv m184v mutation nrti lamivudine reverse zidovudine level rna k65r transcriptase mutations stavudine source

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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