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Management of NRTI Resistance

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Presentation on theme: "Management of NRTI Resistance"— Presentation transcript:

1 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

2 NRTI Resistance: Outline
Mechanism of NRTI Resistance M184V Mutation Thymidine Analog Mutations (TAMs) K65R Mutation

3 Mechanisms of NRTI Resistance
Resistance to Nucleoside Reverse Transcriptase Inhibitors Mechanisms of NRTI Resistance

4 HIV Reverse Transcription Conversion of HIV RNA to HIV DNA
Reverse Transcriptase HIV DNA

5 HIV Reverse Transcription
HIV DNA HIV RNA Reverse Transcriptase

6 HIV Reverse Transcription
Nucleotides (human) Reverse Transcriptase HIV DNA HIV RNA

7 HIV Reverse Transcription
Nucleotides (human) Reverse Transcriptase Primer HIV DNA HIV RNA Template

8 Inhibition of HIV Reverse Transcription NRTI Mechanism of Action
Nucleotides NRTI Reverse Transcriptase (1) Incorporation of NRTI Primer (2) Primer Blocking HIV DNA HIV RNA Template

9 Inhibition of HIV Reverse Transcription NRTI Mechanism of Action
Nucleotides NRTI Reverse Transcriptase HIV DNA Chain Termination HIV RNA

10 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.

11 Biochemical Mechanisms of NRTI Resistance (1) Discrimination Pathway
Enhanced discrimination against NRTIs and decreased incorporation of NRTIs in favor of host nucleotides Nucleotides NRTI Enhanced Incorporation of Host Nucleotides Decreased Incorporation of NRTI HIV DNA HIV RNA Reverse Transcriptase

12 Biochemical Mechanisms of NRTI Resistance (2) Excision Pathway
Excision of incorporated NRTI by promoting pyrophosphorolysis (primer unblocking) Nucleotides NRTI Excision (Primer Unblocking) HIV DNA HIV RNA Reverse Transcriptase

13 Common NRTI Resistance Mutations
Resistance to Nucleoside Reverse Transcriptase Inhibitors Common NRTI Resistance Mutations

14 High-Level Resistance Increased Susceptibility
Wild Type HIV-1: NRTIs Wild Type HIV Tenofovir Zidovudine Stavudine Abacavir Didanosine Lamivudine Emtricitabine High-Level Resistance Low-Level Resistance Increased Susceptibility

15 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?

16 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, ESS4001 Source: Gupta R, et al. Clin Infect Dis ;47:

17 Treatment time (weeks)
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 4 8 12 16 20 24 28 32 36 40 44 48 52 Lamivudine 300 mg BID only Lamivudine Resistance (M184V) Change in HIV RNA (Log10) Source: Eron JJ, et al. N Engl J Med 1995;333:

18 High-Level Resistance Increased Susceptibility
M184V/I Mutation M184V/I Mutation Tenofovir Zidovudine Stavudine Abacavir Didanosine Lamivudine Emtricitabine High-Level Resistance Low-Level Resistance Increased Susceptibility

19 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 Total Source: Stanford University: HIV Drug Resistance Database (accessed 6/9/2015)

20 Lamivudine Monotherapy versus Treatment Interruption in Patients with M184V Mutation
Patients on failing therapy requesting treatment interruption CD4 > 500 cells/mm3 HIV RNA > 1,000 copies/ml M184V Mutation n = 58 All ARV Meds Discontinued n = 29 Lamivudine 300 mg qd n = 29 Resume Therapy - CD4 < CDC B or C Event Source: Castagna A, et al. AIDS. 2006;20:

21 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 Source: Castagna A, et al. AIDS. 2006;20:

22 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

23 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?

24 Thymidine Analog Mutations (TAMs)
Thymidine Analogs Thymidine Analog Mutations Zidovudine Stavudine M41L D67N K70R L210W T215YF K219QE

25 High-Level Resistance Increased Susceptibility
M184V/I and Multiple TAMs M184V/I + 3TAMs (M41L, L210W, T215Y) Tenofovir Zidovudine Stavudine Abacavir Didanosine Lamivudine Emtricitabine High-Level Resistance Low-Level Resistance Increased Susceptibility

26 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 M184V 60 -10 L210W T215Y 45 T215Y + M41L – T210W + T215Y T210W + M41L Total 75 80 95 55 Source: Stanford University: HIV Drug Resistance Database (accessed 11/18/2014)

27 Thymidine Analog Mutations (TAMs)
Wild Type HIV Zidovudine or Stavudine M41L L210W T215Y/F K70R K219Q/E D67N Thymidine Analog Mutations (TAMs)

28 Distinct TAM Pathways to Resistance
Zidovudine or Stavudine Type-1 TAM Pattern Type-2 TAM Pattern D67N M41L K70R L210W T215F T215Y K219Q/E Source: Shafer RW, Schapiro JM. AIDS Rev. 2008;10:67-84.

29 Distinct TAM Pathways to Resistance
Zidovudine or Stavudine Type-1 TAM Pattern Type-2 TAM Pattern D67N M41L K70R L210W T215F T215Y K219Q/E 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 Source: Shafer RW, Schapiro JM. AIDS Rev.2008;10:67-84.

30 Resistance Pathway with Thymidine Analog + Lamivudine
Zidovudine + Lamivudine or Stavudine + Lamivudine M184V/I Type-1 TAM Pattern Type-2 TAM Pattern M41L D67N L210W K70R T215F T215Y K219Q/E

31 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?

32 High-Level Resistance Increased Susceptibility
K65R Mutation K65R Mutation Tenofovir Zidovudine Stavudine Abacavir Didanosine Lamivudine Emtricitabine High-Level Resistance Low-Level Resistance Increased Susceptibility

33 K65R Mutation Score Mutation Scoring: Stanford HIV Drug Resistance Database RT 3TC ABC AZT D4T DDI FTC TDF K65R 30 45 -15 60 Total Source: Stanford University: HIV Drug Resistance Database (accessed 6/9/2015)

34 Resistance Pathway with Tenofovir + Emtricitabine
M184V/I K65R

35 Resistance Pathway with Abacavir + Lamivudine
M184V/I L74V K65R

36 High-Level Resistance Increased Susceptibility
M184V/I + K65R Mutations M184V/I + K65R Mutations Tenofovir Zidovudine Stavudine Abacavir Didanosine Lamivudine Emtricitabine High-Level Resistance Low-Level Resistance Increased Susceptibility

37 M184V/I + K65R Mutation Score
Mutation Scoring: Stanford HIV Drug Resistance Database RT 3TC ABC AZT D4T DDI FTC TDF K65R 30 45 -15 60 M184V 15 -10 10 K65R + M184V – Total 90 -25 70 Source: Stanford University: HIV Drug Resistance Database (accessed 11/18/2014)

38 NRTI Resistance: Summary
Resistance to Nucleoside Reverse Transcriptase Inhibitors NRTI Resistance: Summary

39 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

40 Questions 1

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