Presentation is loading. Please wait.

Presentation is loading. Please wait.

NNRTI Resistance David H. Spach, MD Principal Investigator, NW AETC

Published byMarylou Blake Modified over 9 years ago

Similar presentations

Presentation on theme: "NNRTI Resistance David H. Spach, MD Principal Investigator, NW AETC"— Presentation transcript:

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

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

4 HIV Reverse Transcriptase
Polymerase Active Site p51 Reverse Transcriptase

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

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

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

8 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

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

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

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

12 Common NNRTI Resistance Mutations
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-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?

14 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 :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 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 ;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 STARTMRK3 - K103N > M184V 1Study 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 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

18 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

19 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

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

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 45 30 60 K101E 15 K103N G190S Total 180 195 105 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 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:

24 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:

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

Download ppt "NNRTI Resistance David H. Spach, MD Principal Investigator, NW AETC"

Similar presentations

M ANAGING ARV REGIMEN FAILURE IN THE HIV INFECTED CHILD Dr L Keet Centre of Excellence HIV Directorate.

M ANAGING ARV REGIMEN FAILURE IN THE HIV INFECTED CHILD Dr L Keet Centre of Excellence HIV Directorate.
New Antiretrovirals for the Treatment of HIV. Convenience, tolerability, simplicity New & Investigational Agents.

New Antiretrovirals for the Treatment of HIV. Convenience, tolerability, simplicity New & Investigational Agents.
TMC278 Update, 30th January 2009  C204 data  ECHO and THRIVE - Phase III studies  New TMC278 formulations Peter Williams Tibotec BVBA, Mechelen, Belgium.

TMC278 Update, 30th January 2009  C204 data  ECHO and THRIVE - Phase III studies  New TMC278 formulations Peter Williams Tibotec BVBA, Mechelen, Belgium.
Initiating Antiretroviral Therapy in Treatment-Naive Patients Charles B. Hicks, MD Associate Professor of Medicine, Division of Infectious Diseases and.

Initiating Antiretroviral Therapy in Treatment-Naive Patients Charles B. Hicks, MD Associate Professor of Medicine, Division of Infectious Diseases and.
N ORTHWEST A IDS E DUCATION AND T RAINING C ENTER Crafting an ART Regimen for Initiation or Salvage: Are NRTI’s Necessary? Brian R. Wood, MD Assistant.

N ORTHWEST A IDS E DUCATION AND T RAINING C ENTER Crafting an ART Regimen for Initiation or Salvage: Are NRTI’s Necessary? Brian R. Wood, MD Assistant.
+ Antiretroviral Agents: HIV & AIDS Shaw Vonder Hoya.

+ Antiretroviral Agents: HIV & AIDS Shaw Vonder Hoya.
HIV Lifecycle and Mechanisms of Antiretroviral Therapy

HIV Lifecycle and Mechanisms of Antiretroviral Therapy
Dr Emmanuel Nsutebu Consultant Infectious Diseases Physician Tropical and Infectious Diseases Unit Royal Liverpool Hospital HIV “Myths, controversies and.

Dr Emmanuel Nsutebu Consultant Infectious Diseases Physician Tropical and Infectious Diseases Unit Royal Liverpool Hospital HIV “Myths, controversies and.
Salvage Antiretroviral Therapy Guiding Principles, Strategies and the Role of Resistance Testing.

Salvage Antiretroviral Therapy Guiding Principles, Strategies and the Role of Resistance Testing.
N ORTHWEST A IDS E DUCATION AND T RAINING C ENTER 2014 IAS-USA Treatment Guidelines Brian R. Wood, MD Medical Director, NW AETC ECHO Assistant Professor.

N ORTHWEST A IDS E DUCATION AND T RAINING C ENTER 2014 IAS-USA Treatment Guidelines Brian R. Wood, MD Medical Director, NW AETC ECHO Assistant Professor.
DHS/HIV/PP HIV/AIDS 2007 Update David H. Spach, MD Clinical Director Northwest AIDS Education and Training Center Professor of Medicine Division of Infectious.

DHS/HIV/PP HIV/AIDS 2007 Update David H. Spach, MD Clinical Director Northwest AIDS Education and Training Center Professor of Medicine Division of Infectious.
ANTIRETROVIRAL RESISTANCE Jennifer Fulcher, MD, PhD.

ANTIRETROVIRAL RESISTANCE Jennifer Fulcher, MD, PhD.
Failure Therapy VIRAL RESITANCE ADHERENCE!!!!!!!!!!! DRUG INTERACTION.

Failure Therapy VIRAL RESITANCE ADHERENCE!!!!!!!!!!! DRUG INTERACTION.
1 Review of Antiretroviral Therapy in Adults HAIVN Harvard Medical School AIDS Initiative in Vietnam.

1 Review of Antiretroviral Therapy in Adults HAIVN Harvard Medical School AIDS Initiative in Vietnam.
Case 1: 23-year-old Male Student Clinical Director, Division of Infectious Diseases Brigham and Women’s Hospital Professor of Medicine Harvard Medical.

Case 1: 23-year-old Male Student Clinical Director, Division of Infectious Diseases Brigham and Women’s Hospital Professor of Medicine Harvard Medical.
© 2011. IAS–USA Johnson VA et al. Top Antivir Med. 2011;19(4):156-164. Updates, user notes, and references available at www.iasusa.org. Mutations in the.

© IAS–USA Johnson VA et al. Top Antivir Med. 2011;19(4): Updates, user notes, and references available at Mutations in the.
Predicting NNRTI Resistance – do polymorphisms matter? Nicola E Mackie 1, Lucy Garvey 1, Anna Maria Geretti 2, Linda Harrison 3, Peter Tilston 4, Andrew.

Predicting NNRTI Resistance – do polymorphisms matter? Nicola E Mackie 1, Lucy Garvey 1, Anna Maria Geretti 2, Linda Harrison 3, Peter Tilston 4, Andrew.
Increased phenotypic susceptibility (hypersusceptibility, HS) to NNRTIs is observed in ~30% of viral isolates with NRTI- resistance mutations 1 and has.

Increased phenotypic susceptibility (hypersusceptibility, HS) to NNRTIs is observed in ~30% of viral isolates with NRTI- resistance mutations 1 and has.
1 Introduction to ARV Therapy HAIVN Harvard Medical School AIDS Initiative in Vietnam.

1 Introduction to ARV Therapy HAIVN Harvard Medical School AIDS Initiative in Vietnam.
HIV Principles in Primary Care and Triage of the HIV patient David Aymond, MD, AAHIVM.

HIV Principles in Primary Care and Triage of the HIV patient David Aymond, MD, AAHIVM.

Similar presentations

Ads by Google