NORTHWEST AIDS EDUCATION AND TRAINING CENTER

Second-Line Therapy David Spach, MD Clinical Director, Northwest AETC Professor of Medicine, Division of Infectious Diseases University of Washington Presentation Prepared by: David Spach, MD Last Updated: May 14, 2012

Class Therapy Pill Burden

NNRTI-Based Efavirenz-Tenofovir-Emtricitabine

PI-Based

Ritonavir + Atazanavir + Tenofovir-Emtricitabine

Darunavir + Ritonavir + Tenofovir-Emtricitabine

INSTI-Based Raltegravir + Tenofovir-Emtricitabine

HHS Antiretroviral Therapy Guidelines: March 2012 Preferred Regimens for ARV-Naïve Patients: Pill Burden

Source: 2012 HHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)

2NRTIs + NNRTI

2 NRTIs + RTV-boosted PI

2 NRTIs + INSTI

or

or

Virologic Failure after Initial Therapy

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Case History

•  A 29-year-old woman with a baseline CD4 count of 285 cells/mm3 and HIV RNA 94,000 copies/ml starts on a regimen of tenofovir-emtricitabine-efavirenz (Atripla). After 4 months, she has an HIV RNA of less than 40 copies/ml and she does very well on this regimen for about 10 months. After missing two appointments, she comes in for follow-up visit and admits she had a relapse with her alcohol problem, but is now sober. Her HIV RNA drawn at this routine visit is 1120 copies/ml.

•  What is the treatment goal of second-line therapy?

•  What mutations would you expect on a genotype?

•  What second-line regimen would you recommend (if needed)?

HHS Antiretroviral Therapy Guidelines: March 2012 Goal in Treatment-Experienced Patients

•  Treatment Goal for Patients with Prior Drug Exposure & Drug Resistance: -Re-establish maximal virologic suppression (HIV-1 RNA < 50 copies/mL)

Source: HHS Antiretroviral Therapy Guidelines. March, 2012.

10

100

1,000

10,000

100,000

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64

HIV

RN

A (c

opie

s/m

l)

Weeks

ART Started

Salvage ART

Virologic Failure on Tenofovir-Emtricitabine-Efavirenz Resistance Mutations

•  Study 9341 - K103N > M184V/I + K103N > Other NNRTI mutations

•  ACTG 51422 - K103N > M184V > K65R > 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.

K65R: Tenofovir M184V: Emtricitabine/Lamivdine K103N: Efavirenz

NNRTI Resistance: Wild Type HIV-1

Efavirenz

Etravirine

Nevirapine

High-Level Resistance

Increased Susceptibility

Rilpivirine

Wild Type

Impact of K103N on NNRTIs

Efavirenz

Etravirine

Nevirapine

Rilpivirine

High-Level Resistance

Increased Susceptibility

Wild Type

NRTIs: Wild Type HIV-1

Lamivudine

Emtricitabine

Didanosine

Abacavir

Zidovudine

Stavudine

Tenofovir

High-Level Resistance

Increased Susceptibility

Wild Type

Impact of M184V Mutation on NRTIs

Lamivudine

Emtricitabine

Didanosine

Abacavir

Zidovudine

Stavudine

Tenofovir

High-Level Resistance

Increased Susceptibility

Wild Type

Tenofovir-Emtricitabine-Efavirenz

2 NRTIs + RTV-boosted PI

2 NRTIs + Raltegravir

Virologic Failure with NNRTI in Initial Regimen Subsequent Therapy: Options

2 NRTIs + Etravirine

1-2 NRTIs + 2 Drugs from 2 other classes

Tenofovir-Emtricitabine-Efavirenz

2 NRTIs + RTV-boosted PI

1-2 NRTIs + 2 Drugs from 2 other classes

Virologic Failure with NNRTI in Initial Regimen Subsequent Therapy: Preferred Options

Examples of 2 Drugs from 2 other classes: Raltegravir + Maraviroc Raltegravir + Etravirine Maraviroc + Etravirine

1

2

Once Daily versus Twice Daily Darunavir in ARV-Experienced ODIN Trial: 48 Week Results

Source: Cahn P, et al. AIDS. 2011 Feb 22. [Epub ahead of print]

Darunavir 600 mg bid + Ritonavir 100 mg bid + OBR (n = 296)

Darunavir 800 mg qd + Ritonavir 100 mg qd + OBR (n = 294)

Study Features

N = 590 Adults Randomized, open label Treatment experienced* Stable HAART > 12 weeks HIV RNA > 1,000 copies/mL CD4 > 50 cells/mm3 No Darunavir-associated mutations OBR^ included > 2 active NRTIs

0 48 Randomize Analysis

Study Week

*46% protease inhibitor naïve *Primary PI mutations in < 2% of patients in each arm of study ^OBR = Optimized Background Regimen (optimized NRTIs)

Once Daily versus Twice Daily Darunavir in ARV-Experienced ODIN Trial: 48 Week Results

Week 48: Virologic Response ( ITT-TLOVR*)

Source: Cahn P, et al. AIDS. 2011 Feb 22. [Epub ahead of print]

72.1 78.4

52.8

70.9 76.8

52.8

0

20

40

60

80

100

All Baseline HIV RNA ≤50,000 copies/ml

Baseline HIV RNA > 50,000 copies/ml

Patie

nts

(%) w

ith H

IV R

NA

< 50

co

pies

/ml

Darunavir-Ritonavir qd + OBR Darunavir-Ritonavir bid + OBR

2 NRTIs + RTV-boosted PI

Virologic Failure with Protease Inhibitor in Initial Regimen Subsequent Therapy: Options

1-2 NRTIs + 2 Drugs from 2 classes

2 NRTIs + NNRTI

2 NRTIs + Raltegravir

2 NRTIs + RTV-boosted PI

Examples of 2 Drugs from 2 other classes: Raltegravir + Maraviroc Raltegravir + Etravirine Maraviroc + Etravirine

Virologic Failure with PI in Initial Regimen Subsequent Therapy

•  Limited data on optimal approach

•  PI mutations uncommon early on genotype with 1st failure

•  M184V most common NRTI mutation with 1st failure

•  Reexamine tolerability and dosing schedule

•  Data suggest darunavir effective in most PI-experienced

International AIDS Society USA (IAS-USA) 2011 Darunavir Resistance-Associated Mutations (DRV RAMs)

Source: Johnson VA, et al. Top HIV Med. 2011;19:156-64.

IAS-USA Darunavir RAMs

Major Minor

I47V

I50V

I54L

I54M

L76V

I84V

V11I

V32I

L33F

T74P

L89V

Baseline Darunavir Resistance-Associated Mutations and Treatment Response: TITAN Study

TITAN: Week 48 Virologic Response

Source: de Meyer S, et al. AIDS. 2009;23:1829-40.

82 82 83 78

60

0

20

40

60

80

100

All 0 1 2 ≥3

Patie

nts

(%):

HIV

RN

A <

50 c

opie

s/m

l

Number of Baseline Darunavir Resistance-Associated Mutations

DRV RAMs V11I V32I L33F I47V I50V I54L I54M G73S L76V I84V L89V

Tenofovir-Emtricitabine + Raltegravir

2 NRTIs + RTV-boosted PI

Virologic Failure with Raltegravir in Initial Regimen Subsequent Therapy: Options

2 NRTIs + NNRTIs

1-2 NRTIs + 2 Drugs from 2 other classes

2 NRTIs + Elvitegravir

Source: Fransen S, et al. J Virol. 2009;83:11440-6.

Major Pathways of Resistance with Raltegravir

Raltegravir

N155H

Q148H/K/R

Secondary Mutations (L74M, E92Q, T97A, V151I, G163R)

Secondary Mutations (L74M, G140A/S, E138K)

Early

Delayed

Evolution of Integrase Resistance During INSTI Failure SCOPE Study

Source: Hatono H, et al. J Acquir Immune Defic Syndr. 2010;54:389-93.

0

20

40

60

80

100

0 1 2 3

Perc

enta

ge o

f Sub

ject

s w

ih

Res

ista

nce

Mut

atio

ns

Visit

0 1 2 3+

Number of Mutations

Virologic Failure with Raltegravir in Initial Regimen Subsequent Therapy

•  Resistance to raltegravir evolves progressively

•  Avoid prolonged failure

•  Integrase genotype may be helpful for 2nd generation ISTIs

•  M184V often precedes raltegravir resistance

•  Boosted protease-inhibitor regimens should be effective

•  Cross resistance common with elvitegravir

•  Dolutegravir likely to be effective unless failure prolonged

Summary Points

•  Goal of second-line therapy: HIV RNA < 50 copies/ml

•  Avoid prolonged virologic failure

•  Tenofovir-emtricitabine-efavirenz failure can usually be managed with ritonavir-boosted PI

•  Early ritonavir-boosted PI failure often not associated with PI mutations

•  Tenofovir-emtricitabine + raltegravir failure can usually be managed with ritonavir-boosted PI

Questions?