NNRTI Resistance NORTHWEST AIDS EDUCATION AND TRAINING CENTER
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1 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
2 RESISTANCE TO NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS NNRTI Mechanisms of Action
3 HIV Reverse Transcription Conversion of HIV RNA to HIV DNA HIV RNA Reverse Transcription Reverse Transcriptase HIV DNA
4 HIV Reverse Transcriptase p66 Polymerase Active Site p51 Reverse Transcriptase
5 HIV Reverse Transcriptase p66 Polymerase Active Site Fingers Thumb Palm p51 Reverse Transcriptase
6 HIV Reverse Transcription HIV DNA Polymerase Active Site HIV RNA Reverse Transcriptase
7 Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Polymerase Active Site NNRTI Binding Pocket Reverse Transcriptase
8 Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) NNRTI Inhibitor Polymerase Active Site NNRTI Binding Pocket Reverse Transcriptase
9 Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) NNRTI Inhibitor Altered Polymerase Active Site Hyperextended thumb region Reverse Transcriptase
10 Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) E138 Reverse Transcriptase NNRTI Binding Pocket
11 Resistance to NNRTIs NNRTI Inhibitor Polymerase Active Site Common Resistance Mutations Reverse Transcriptase
12 RESISTANCE TO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Common NNRTI Resistance Mutations
13 Case Histories One afternoon in clinic, two patients with virologic failure are seen. Patient 1: 31-year-old man taking tenofovir-emtricitabineefavirenz (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-emtricitabinerilpivirine (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?
14 2NRTIs + (Efavirenz or Rilpivirine) in ARV-Naive ECHO and THRIVE Pooled Data: Study Design ECHO Efavirenz: 600 mg qd + TDF/FTC (n = 344) Rilpivirine: 25 mg qd + TDF/FTC (n = 346) THRIVE Efavirenz: 600 mg qd + *2NRTIs (n = 338) Rilpivirine: 25 mg qd + *2NRTIs (n = 340) *2 NRTIs: Tenofovir + Emtricitabine; Zidovudine + Lamivudine; Abacavir + Lamivudine Source: Cohen C, et al. J Acquir Immune Defic Syndr. 2012:60:33-42.
15 2NRTIs + (Efavirenz or Rilpivirine) in ARV-Naive ECHO and THRIVE Pooled Data: Study Design Resistance Findings in ECHO and THRIVE Studies: 48 Week Data Efavirenz (N = 682) Rilpivirine (N = 686) Virologic failure with resistance data, n 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%) Source: Cohen C, et al. J Acquir Immune Defic Syndr. 2012;60:33-42.
16 Virologic Failure with Efavirenz HIV Resistance Genotype Data Study K103N > M184V/I + K103N > Other NNRTI mutations ACTG K103N > M184V > K65RN > Other NNRTI mutations STARTMRK 3 - K103N > M184V 1 Study 934: Gallant JE, et al. N Engl J Med. 2006;354: Study Riddler SA, et al. N Engl J Med. 2008;358; STARTMRK. Lennox JL, et al. Lancet. 2009;374:
17 Wild Type HIV-1 Wild Type HIV Efavirenz Etravirine Nevirapine Rilpivirine High-Level Resistance Intermediate Resistance Low-Level Resistance Increased Susceptibility
18 Impact of K103N Mutation K103N Efavirenz Etravirine Nevirapine Rilpivirine High-Level Resistance Intermediate Resistance Low-Level Resistance Increased Susceptibility
19 Impact of E138K Mutation E138K Efavirenz Etravirine Nevirapine Rilpivirine High-Level Resistance Intermediate Resistance Low-Level Resistance Increased Susceptibility
20 Impact of E138K + M184I Mutation E138K + M184I Efavirenz Etravirine Nevirapine Rilpivirine High-Level Resistance Intermediate Resistance Low-Level Resistance Increased Susceptibility
21 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?
22 Multiple NNRTI Resistance Mutations Mutation Scoring: Stanford HIV Drug Resistance Database RT Efavirenz Etravirine Nevirapine Rilpivirine L100I K101E K103N G190S Total Source: Stanford University: HIV Drug Resistance Database (accessed 2/20/2015)
23 Weighted Scores for Etravirine-Associated Mutations Based on Data from Duet 1 & 2 Individual Mutation Weight to Etravirine V90I V106I L100I Y181I A98G E138A K101P Y181V K101E K101H V179D V179T G190A V179F G190S Y181C M230L Source: Vingerhoets J, et al. AIDS. 2010;24:
24 Weighted Scores for Etravirine-Associated Mutations Based on Data from Duet 1 & 2 Individual Mutation Weight to Etravirine V90I V106I L100I Y181I A98G E138A K101P Y181V K101E K101H V179D V179T G190A V179F G190S Y181C M230L L100I (2.5), K101E (1.0), K103N (0), and G190S (1.5) = Weighted Score of 5 Source: Vingerhoets J, et al. AIDS. 2010;24:
25 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 Highest Response Intermediate Response Reduced Response HIV RNA < 50 copies/ml Etravirine Genotypic Susceptibility Score Source: Vingerhoets J, et al. AIDS. 2010;24:
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