nnrti resistance - university of washington
TRANSCRIPT
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NORTHWEST AIDS EDUCATION AND TRAINING CENTER
NNRTI Resistance David H. Spach, MD Principal Investigator, NW AETC Professor of Medicine, Division of Infectious Diseases University of Washington Last Updated: February 23, 2015
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NNRTI Mechanisms of Action RESISTANCE TO NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
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HIV Reverse Transcription Conversion of HIV RNA to HIV DNA
HIV DNA
HIV RNA
Reverse Transcription
Reverse Transcriptase
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HIV Reverse Transcriptase
p66
Reverse Transcriptase
p51
Polymerase Active Site
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HIV Reverse Transcriptase
p66
Reverse Transcriptase
p51
Polymerase Active Site
Thumb
Fingers
Palm
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HIV Reverse Transcription
HIV DNA
HIV RNA
Reverse Transcriptase
Polymerase Active Site
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Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI)
Reverse Transcriptase
NNRTI Binding Pocket
Polymerase Active Site
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Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI)
Reverse Transcriptase
NNRTI Binding Pocket
Polymerase Active Site
NNRTI Inhibitor
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Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI)
Reverse Transcriptase
Altered Polymerase Active Site
NNRTI Inhibitor
Hyperextended thumb region
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Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI)
Reverse Transcriptase NNRTI Binding Pocket
E138
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Resistance to NNRTIs
Reverse Transcriptase
NNRTI Inhibitor
Common Resistance Mutations
Polymerase Active Site
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Common NNRTI Resistance Mutations RESISTANCE TO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
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Case Histories
• One afternoon in clinic, two patients with virologic failure are seen.
• Patient 1: 31-year-old man taking tenofovir-emtricitabine-efavirenz (Atripla) and the most recent two HIV RNA levels are 976 and 1,645 copies/ml. A genotype is ordered.
• Patient 2:26-year-old woman taking tenofovir-emtricitabine-rilpivirine (Complera) and the most recent two HIV RNA levels are 648 and 1,220 copies/ml. A genotype is ordered.
• What would you expect to find on the genotype for: Patient 1? Patient 2?
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2NRTIs + (Efavirenz or Rilpivirine) in ARV-Naive ECHO and THRIVE Pooled Data: Study Design
Source: Cohen C, et al. J Acquir Immune Defic Syndr. 2012:60:33-42.
ECHO
THRIVE
*2 NRTIs: Tenofovir + Emtricitabine; Zidovudine + Lamivudine; Abacavir + Lamivudine
Efavirenz: 600 mg qd + TDF/FTC (n = 344)
Rilpivirine: 25 mg qd + TDF/FTC (n = 346)
Efavirenz: 600 mg qd + *2NRTIs (n = 338)
Rilpivirine: 25 mg qd + *2NRTIs (n = 340)
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2NRTIs + (Efavirenz or Rilpivirine) in ARV-Naive ECHO and THRIVE Pooled Data: Study Design
Source: Cohen C, et al. J Acquir Immune Defic Syndr. 2012;60:33-42.
Resistance Findings in ECHO and THRIVE Studies: 48 Week Data
Efavirenz (N = 682)
Rilpivirine (N = 686)
Virologic failure with resistance data, n 28 62
Emergent NNRTI RAMs 54% 63%
Most Frequent NNRTI RAMs K103N (73%) E138K (72%)
Emergent NRTI RAMs 32% 68%
Most Frequent NRTI RAMs M184V (67%) M184I (69%)
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Virologic Failure with Efavirenz HIV Resistance Genotype Data
• Study 9341 - K103N > M184V/I + K103N > Other NNRTI mutations
• ACTG 51422 - K103N > M184V > K65RN > Other NNRTI mutations
• STARTMRK3 - K103N > M184V
1Study 934: Gallant JE, et al. N Engl J Med. 2006;354:251-60. 2Study 5142. Riddler SA, et al. N Engl J Med. 2008;358;2095-106. 3STARTMRK. Lennox JL, et al. Lancet. 2009;374:796-806.
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Wild Type HIV-1
High-Level Resistance
Low-Level Resistance
Increased Susceptibility
Intermediate Resistance
Wild Type HIV
Nevirapine
Rilpivirine
Efavirenz
Etravirine
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Impact of K103N Mutation
High-Level Resistance
Low-Level Resistance
Increased Susceptibility
Intermediate Resistance
K103N
Nevirapine
Rilpivirine
Efavirenz
Etravirine
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Impact of E138K Mutation
E138K
High-Level Resistance
Low-Level Resistance
Increased Susceptibility
Intermediate Resistance
Nevirapine
Rilpivirine
Efavirenz
Etravirine
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Impact of E138K + M184I Mutation
High-Level Resistance
Low-Level Resistance
Increased Susceptibility
Intermediate Resistance
E138K + M184I
Nevirapine
Rilpivirine
Efavirenz
Etravirine
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Case History
• A 46-year-old man is seen in the clinic for evaluation of a salvage antiretroviral regimen. He an has extensive antiretroviral treatment history with multiple episodes of virologic failure.
• A deep salvage regimen is being considered and the most recent HIV genotype resistance test shows multi-drug class resistance including the following NNRTI-related mutations: - L100I, K101E, K103N, and G190S
• Do you think any NNRTI medications will likely be effective in a salvage regimen?
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Source: Stanford University: HIV Drug Resistance Database (accessed 2/20/2015)
Multiple NNRTI Resistance Mutations
Mutation Scoring: Stanford HIV Drug Resistance Database
RT Efavirenz Etravirine Nevirapine Rilpivirine
L100I 45 30 45 60
K101E 15 15 30 30
K103N 60 0 60 0
G190S 60 15 60 15
Total 180 60 195 105
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Weighted Scores for Etravirine-Associated Mutations Based on Data from Duet 1 & 2
Source: Vingerhoets J, et al. AIDS. 2010;24:503-14.
Individual Mutation Weight to Etravirine
1.0 1.5 2.5 3 V90I
A98G
K101E
K101H
V179D
V179T
G190A
V106I
E138A
V179F
G190S
L100I
K101P
Y181C
M230L
Y181I
Y181V
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Source: Vingerhoets J, et al. AIDS. 2010;24:503-14.
Weighted Scores for Etravirine-Associated Mutations Based on Data from Duet 1 & 2
Individual Mutation Weight to Etravirine
1.0 1.5 2.5 3 V90I
A98G
K101E
K101H
V179D
V179T
G190A
V106I
E138A
V179F
G190S
L100I
K101P
Y181C
M230L
Y181I
Y181V
L100I (2.5), K101E (1.0), K103N (0), and G190S (1.5) = Weighted Score of 5
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Weighted Scores for Etravirine-Associated Mutations Based on Data from Duet 1 & 2
Duet-1 and Duet-2: Etravirine Susceptibility Score and Virologic Response at Week 24
Source: Vingerhoets J, et al. AIDS. 2010;24:503-14.
74.4
52.0
37.7
0
20
40
60
80
100
0.0-2.0 2.5-3.5 ≥ 4.0
HIV
RN
A <
50 c
opie
s/m
l
Etravirine Genotypic Susceptibility Score
Highest Response Intermediate Response Reduced Response