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

NNRTI Mechanisms of Action RESISTANCE TO NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

HIV Reverse Transcription Conversion of HIV RNA to HIV DNA

HIV DNA

HIV RNA

Reverse Transcription

Reverse Transcriptase

HIV Reverse Transcriptase

p66

Reverse Transcriptase

p51

Polymerase Active Site

HIV Reverse Transcriptase

p66

Reverse Transcriptase

p51

Polymerase Active Site

Thumb

Fingers

Palm

HIV Reverse Transcription

HIV DNA

HIV RNA

Reverse Transcriptase

Polymerase Active Site

Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI)

Reverse Transcriptase

NNRTI Binding Pocket

Polymerase Active Site

Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI)

Reverse Transcriptase

NNRTI Binding Pocket

Polymerase Active Site

NNRTI Inhibitor

Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI)

Reverse Transcriptase

Altered Polymerase Active Site

NNRTI Inhibitor

Hyperextended thumb region

Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI)

Reverse Transcriptase NNRTI Binding Pocket

E138

Resistance to NNRTIs

Reverse Transcriptase

NNRTI Inhibitor

Common Resistance Mutations

Polymerase Active Site

Common NNRTI Resistance Mutations RESISTANCE TO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

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 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.

Wild Type HIV-1

High-Level Resistance

Low-Level Resistance

Increased Susceptibility

Intermediate Resistance

Wild Type HIV

Nevirapine

Rilpivirine

Efavirenz

Etravirine

Impact of K103N Mutation

High-Level Resistance

Low-Level Resistance

Increased Susceptibility

Intermediate Resistance

K103N

Nevirapine

Rilpivirine

Efavirenz

Etravirine

Impact of E138K Mutation

E138K

High-Level Resistance

Low-Level Resistance

Increased Susceptibility

Intermediate Resistance

Nevirapine

Rilpivirine

Efavirenz

Etravirine

Impact of E138K + M184I Mutation

High-Level Resistance

Low-Level Resistance

Increased Susceptibility

Intermediate Resistance

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.

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