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

NNRTI Mechanisms of Action Resistance to Non-Nucleoside Reverse Transcriptase Inhibitors NNRTI Mechanisms of Action

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

HIV Reverse Transcriptase Polymerase Active Site p51 Reverse Transcriptase

HIV Reverse Transcriptase Thumb Fingers Palm p66 Polymerase Active Site p51 Reverse Transcriptase

HIV Reverse Transcription HIV DNA Polymerase Active Site HIV RNA Reverse Transcriptase

Polymerase Active Site Reverse Transcriptase Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Polymerase Active Site NNRTI Binding Pocket Reverse Transcriptase

Polymerase Active Site Reverse Transcriptase Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) NNRTI Inhibitor Polymerase Active Site NNRTI Binding Pocket Reverse Transcriptase

Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Altered Polymerase Active Site NNRTI Inhibitor Hyperextended thumb region

Reverse Transcriptase Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) E138 Reverse Transcriptase NNRTI Binding Pocket

Resistance to NNRTIs Reverse Transcriptase NNRTI Inhibitor Polymerase Active Site Common Resistance Mutations Reverse Transcriptase

Common NNRTI Resistance Mutations Resistance to Nucleoside Reverse Transcriptase Inhibitors Common NNRTI Resistance Mutations

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 Efavirenz: 600 mg qd + TDF/FTC (n = 344) ECHO Rilpivirine: 25 mg qd + TDF/FTC (n = 346) Efavirenz: 600 mg qd + *2NRTIs (n = 338) THRIVE 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.

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 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%) Source: Cohen C, et al. J Acquir Immune Defic Syndr. 2012;60:33-42.

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.

High-Level Resistance Increased Susceptibility Intermediate Resistance Wild Type HIV-1 Wild Type HIV Efavirenz Etravirine Nevirapine Rilpivirine High-Level Resistance Low-Level Resistance Increased Susceptibility Intermediate Resistance

High-Level Resistance Increased Susceptibility Intermediate Resistance Impact of K103N Mutation K103N Efavirenz Etravirine Nevirapine Rilpivirine High-Level Resistance Low-Level Resistance Increased Susceptibility Intermediate Resistance

High-Level Resistance Increased Susceptibility Intermediate Resistance Impact of E138K Mutation E138K Efavirenz Etravirine Nevirapine Rilpivirine High-Level Resistance Low-Level Resistance Increased Susceptibility Intermediate Resistance

Impact of E138K + M184I Mutation Efavirenz Etravirine Nevirapine Rilpivirine High-Level Resistance Low-Level Resistance Increased Susceptibility Intermediate Resistance

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?

Multiple NNRTI Resistance Mutations Mutation Scoring: Stanford HIV Drug Resistance Database RT Efavirenz Etravirine Nevirapine Rilpivirine L100I 45 30 60 K101E 15 K103N G190S Total 180 195 105 Source: Stanford University: HIV Drug Resistance Database (accessed 2/20/2015)

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 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 Source: Vingerhoets J, et al. AIDS. 2010;24:503-14.

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 Highest Response Intermediate Response Reduced Response Source: Vingerhoets J, et al. AIDS. 2010;24:503-14.