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
Dec 22, 2015
NORTHWEST AIDS EDUCATION AND TRAINING CENTER
NNRTI Resistance
David H. Spach, MDPrincipal Investigator, NW AETCProfessor of Medicine, Division of Infectious DiseasesUniversity of Washington
Last Updated: February 23, 2015
HIV Reverse TranscriptionConversion of HIV RNA to HIV DNA
HIV DNA
HIV RNA
Reverse Transcription
Reverse Transcriptase
Inhibition of HIV Reverse TranscriptionNonnucleoside Reverse Transcriptase Inhibitor (NNRTI)
Reverse Transcriptase
NNRTI Binding Pocket
Polymerase Active Site
Inhibition of HIV Reverse TranscriptionNonnucleoside Reverse Transcriptase Inhibitor (NNRTI)
Reverse Transcriptase
NNRTI Binding Pocket
Polymerase Active Site
NNRTI Inhibitor
Inhibition of HIV Reverse TranscriptionNonnucleoside Reverse Transcriptase Inhibitor (NNRTI)
Reverse Transcriptase
AlteredPolymerase Active Site
NNRTI Inhibitor
Hyperextended thumb region
Inhibition of HIV Reverse TranscriptionNonnucleoside Reverse Transcriptase Inhibitor (NNRTI)
Reverse Transcriptase NNRTI Binding Pocket
E138
Resistance to NNRTIs
Reverse Transcriptase
NNRTI Inhibitor
CommonResistance Mutations
Polymerase Active Site
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?
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)
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%)
Virologic Failure with EfavirenzHIV 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.
Wild Type HIV-1
High-Level Resistance
Low-Level Resistance
IncreasedSusceptibility
IntermediateResistance
Wild Type HIV
Nevirapine
Rilpivirine
Efavirenz
Etravirine
Impact of K103N Mutation
High-Level Resistance
Low-Level Resistance
IncreasedSusceptibility
IntermediateResistance
K103N
Nevirapine
Rilpivirine
Efavirenz
Etravirine
Impact of E138K Mutation
E138K
High-Level Resistance
Low-Level Resistance
IncreasedSusceptibility
IntermediateResistance
Nevirapine
Rilpivirine
Efavirenz
Etravirine
Impact of E138K + M184I Mutation
High-Level Resistance
Low-Level Resistance
IncreasedSusceptibility
IntermediateResistance
E138K + M184I
Nevirapine
Rilpivirine
Efavirenz
Etravirine
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?
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
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
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
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.
0.0-2.0 2.5-3.5 ≥ 4.00
20
40
60
80
100
74.4
52.0
37.7
Etravirine Genotypic Susceptibility Score
HIV
RN
A <
50
co
pie
s/m
l
Highest Response Intermediate Response Reduced Response