Management of NRTI Resistance - University of Washington · 2015-06-19 · Source: Eron JJ, et al. N Engl J Med 1995;333:1662-9. Response to Lamivudine Monotherapy HIV RNA Levels

NORTHWEST AIDS EDUCATION AND TRAINING CENTER

This presentation is intended for educational use only, and does not in any way constitute medical consultation or advice related to any specific patient.

Management of NRTI Resistance 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

M184V Mutation

K65R Mutation

Thymidine Analog Mutations (TAMs)

Mechanisms of NRTI Resistance RESISTANCE TO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

HIV Reverse Transcription Conversion of HIV RNA to HIV DNA

HIV DNA

HIV RNA

Reverse Transcription

Reverse Transcriptase

HIV Reverse Transcription

HIV DNA

HIV RNA



HIV DNA HIV RNA


Nucleotides (human)


HIV DNA HIV RNA


Nucleotides (human)

Template

Primer

Inhibition of HIV Reverse Transcription NRTI Mechanism of Action

HIV DNA HIV RNA

NRTI Nucleotides


(1) Incorporation of NRTI

(2) Primer Blocking

Template

Primer

Inhibition of HIV Reverse Transcription NRTI Mechanism of Action

HIV DNA HIV RNA

NRTI Nucleotides


Chain Termination

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 Pathway

§  Enhanced removal of incorporated NRTI

§  Results from phosphorolytic reaction that leads to primer unblocking

From: Shafer RW, Schapiro JW. AIDS Rev. 2008;10:67-84.

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


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)


Common NRTI Resistance Mutations RESISTANCE TO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Wild Type HIV-1: NRTIs

Lamivudine

Emtricitabine

Didanosine

Abacavir

Zidovudine

Stavudine

Tenofovir

Wild Type HIV

High-Level Resistance

Low-Level Resistance

Increased Susceptibility

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?

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

4.98

2.38

0.03 0.27

0

1

2

3

4

5

6

Major NNRTI

M184V Any TAM K65R

Patie

nts

(%)

Mutation

NNRTI-Based Studies

NNRTI-Based Studies: Study 903, Study 934, COMBINE

0.07

2.98

0.07 0.00 0

1

2

3

4

5

6

Major PI

M184V Any TAM K65R Pa

tient

s (%

)

Mutation

PI-Based Studies

PI-Based Studies ACTG 5142, Study 089, MONARK, Study 863, ESS4001

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 (M184V) Cha

nge

in H

IV R

NA

(Log

10)

M184V/I Mutation

Lamivudine

Emtricitabine

Didanosine

Abacavir

Zidovudine

Stavudine

Tenofovir

M184V/I Mutation




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 -10

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 = 29

Lamivudine 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 Mutation

n = 58

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 Failure 41% 69%

*P = 0.001; **P = 0.002; ***P < 0.001

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 fitness

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, T215Y Protease: D30N, I54L, and L90M

•  What is the significance of the RT mutations M41L, L210W, and T215?


M41L

D67N

K70R

L210W

T215YF

K219QE

Thymidine Analogs Thymidine Analog Mutations

Zidovudine

Stavudine

M184V/I and Multiple TAMs

Lamivudine

Emtricitabine

Didanosine

Abacavir

Zidovudine

Stavudine

Tenofovir




M184V/I + 3TAMs (M41L, L210W, T215Y)


M184V/I and Multiple TAMs (M41L, L210W, T215Y)



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 55


M41L L210W T215Y/F K70R K219Q/E D67N


Wild Type HIV

Zidovudine or Stavudine

Distinct TAM Pathways to Resistance


Source: Shafer RW, Schapiro JM. AIDS Rev. 2008;10:67-84.

Type-1 TAM Pattern Type-2 TAM Pattern

M41L

L210W

T215Y

K70R

K219Q/E

D67N

T215F

Distinct TAM Pathways to Resistance


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


M41L

L210W

T215Y

K70R

K219Q/E

D67N

T215F

Resistance Pathway with Thymidine Analog + Lamivudine

Zidovudine + Lamivudine or Stavudine + Lamivudine


M41L

L210W

T215Y

K70R

K219Q/E

D67N

T215F

M184V/I

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?

K65R Mutation

Didanosine

Abacavir

Stavudine

Tenofovir




K65R Mutation

Lamivudine

Emtricitabine

Zidovudine


K65R Mutation Score



K65R 30 45 -15 45 60 30 60

Total 30 45 -15 45 60 30 60

Resistance Pathway with Tenofovir + Emtricitabine

M184V/I

K65R

Tenofovir + Emtricitabine

Resistance Pathway with Abacavir + Lamivudine

M184V/I

L74V K65R

Abacavir + Lamivudine

M184V/I + K65R Mutations

Lamivudine

Emtricitabine

Didanosine

Abacavir

Zidovudine

Stavudine

Tenofovir




M184V/I + K65R Mutations


M184V/I + K65R Mutation Score



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 60

NRTI Resistance: Summary RESISTANCE TO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

NNRTI Resistance: Summary

•  Two major resistance mechanisms: discrimination and excision

•  M184V common and reduces emtricitabine/lamivudine activity

•  Once M184V develops, maintaining mutation has advantages

•  Multiple TAMs cause broad NRTI resistance

•  K65R has major impact on NRTIs except for zidovudine

•  In most NRTI resistance pathways, M184V develops early

Questions

Documents

Management of NRTI Resistance - University of Washington · 2015-06-19 · Source: Eron JJ, et al. N Engl J Med 1995;333:1662-9. Response to Lamivudine Monotherapy HIV RNA Levels