Second-Line Therapy NORTHWEST AIDS EDUCATION AND TRAINING CENTER

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1 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

2 HHS Antiretroviral Therapy Guidelines: March 2012 Preferred Regimens for ARV-Naïve Patients: Pill Burden Class Therapy Pill Burden NNRTI-Based Efavirenz-Tenofovir-Emtricitabine PI-Based Ritonavir + Atazanavir + Tenofovir-Emtricitabine Darunavir + Ritonavir + Tenofovir-Emtricitabine INSTI-Based Raltegravir + Tenofovir-Emtricitabine Source: 2012 HHS Antiretroviral Therapy Guidelines. AIDS Info (

3 Virologic Failure after Initial Therapy 2NRTIs + NNRTI? or 2 NRTIs + RTV-boosted PI? or 2 NRTIs + INSTI?

4 Case History A 29-year-old woman with a baseline CD4 count of 285 cells/mm 3 and HIV RNA 94,000 copies/ml starts on a regimen of tenofoviremtricitabine-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)?

5 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) 100,000 ART Started HIV RNA (copies/ml) 10,000 1, Salvage ART Weeks Source: HHS Antiretroviral Therapy Guidelines. March, 2012.

6 Virologic Failure on Tenofovir-Emtricitabine-Efavirenz Resistance Mutations Study K103N > M184V/I + K103N > Other NNRTI mutations ACTG K103N > M184V > K65R > Other NNRTI mutations STARTMRK 3 - K103N > M184V K65R: Tenofovir M184V: Emtricitabine/Lamivdine K103N: Efavirenz 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:

7 NNRTI Resistance: Wild Type HIV-1 Efavirenz Etravirine Nevirapine Rilpivirine High-Level Resistance Wild Type Increased Susceptibility

8 Impact of K103N on NNRTIs Efavirenz Etravirine Nevirapine Rilpivirine High-Level Resistance Wild Type Increased Susceptibility

9 NRTIs: Wild Type HIV-1 Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine High-Level Resistance Wild Type Increased Susceptibility

10 Impact of M184V Mutation on NRTIs Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine High-Level Resistance Wild Type Increased Susceptibility

11 Virologic Failure with NNRTI in Initial Regimen Subsequent Therapy: Options 2 NRTIs + RTV-boosted PI Tenofovir-Emtricitabine- Efavirenz 1-2 NRTIs + 2 Drugs from 2 other classes 2 NRTIs + Etravirine 2 NRTIs + Raltegravir

12 Virologic Failure with NNRTI in Initial Regimen Subsequent Therapy: Preferred Options 2 NRTIs + RTV-boosted PI Tenofovir-Emtricitabine- Efavirenz NRTIs + 2 Drugs from 2 other classes Examples of 2 Drugs from 2 other classes: Raltegravir + Maraviroc Raltegravir + Etravirine Maraviroc + Etravirine

13 Once Daily versus Twice Daily Darunavir in ARV-Experienced ODIN Trial: 48 Week Results Study Week 0 48 Randomize Analysis Study Features N = 590 Adults Randomized, open label Treatment experienced* Stable HAART > 12 weeks HIV RNA > 1,000 copies/ml CD4 > 50 cells/mm 3 No Darunavir-associated mutations OBR^ included > 2 active NRTIs Darunavir 800 mg qd + Ritonavir 100 mg qd + OBR (n = 294) Darunavir 600 mg bid + Ritonavir 100 mg bid + OBR (n = 296) *46% protease inhibitor naïve *Primary PI mutations in < 2% of patients in each arm of study ^OBR = Optimized Background Regimen (optimized NRTIs) Source: Cahn P, et al. AIDS Feb 22. [Epub ahead of print]

14 Once Daily versus Twice Daily Darunavir in ARV-Experienced ODIN Trial: 48 Week Results Week 48: Virologic Response ( ITT-TLOVR*) Patients (%) with HIV RNA < 50 copies/ml Darunavir-Ritonavir qd + OBR 72.1 All Baseline HIV RNA 50,000 copies/ml Darunavir-Ritonavir bid + OBR Baseline HIV RNA > 50,000 copies/ml Source: Cahn P, et al. AIDS Feb 22. [Epub ahead of print]

15 Virologic Failure with Protease Inhibitor in Initial Regimen Subsequent Therapy: Options 2 NRTIs + RTV-boosted PI 2 NRTIs + RTV-boosted PI 1-2 NRTIs + 2 Drugs from 2 classes 2 NRTIs + Raltegravir Examples of 2 Drugs from 2 other classes: Raltegravir + Maraviroc Raltegravir + Etravirine Maraviroc + Etravirine 2 NRTIs + NNRTI

16 Virologic Failure with PI in Initial Regimen Subsequent Therapy Limited data on optimal approach PI mutations uncommon early on genotype with 1 st failure M184V most common NRTI mutation with 1 st failure Reexamine tolerability and dosing schedule Data suggest darunavir effective in most PI-experienced

17 International AIDS Society USA (IAS-USA) 2011 Darunavir Resistance-Associated Mutations (DRV RAMs) IAS-USA Darunavir RAMs Major I47V I50V I54L I54M L76V I84V Minor V11I V32I L33F T74P L89V Source: Johnson VA, et al. Top HIV Med. 2011;19:

18 Baseline Darunavir Resistance-Associated Mutations and Treatment Response: TITAN Study TITAN: Week 48 Virologic Response Patients (%): HIV RNA < 50 copies/ml DRV RAMs V11I V32I L33F I47V I50V I54L I54M G73S L76V I84V L89V 0 All Number of Baseline Darunavir Resistance-Associated Mutations Source: de Meyer S, et al. AIDS. 2009;23:

19 Virologic Failure with Raltegravir in Initial Regimen Subsequent Therapy: Options 2 NRTIs + RTV-boosted PI Tenofovir-Emtricitabine + Raltegravir 1-2 NRTIs + 2 Drugs from 2 other classes 2 NRTIs + NNRTIs 2 NRTIs + Elvitegravir

20 Major Pathways of Resistance with Raltegravir Raltegravir Q148H/K/R Delayed Early N155H Secondary Mutations (L74M, E92Q, T97A, V151I, G163R) Secondary Mutations (L74M, G140A/S, E138K) Source: Fransen S, et al. J Virol. 2009;83:

21 Evolution of Integrase Resistance During INSTI Failure SCOPE Study 100 Number of Mutations Percentage of Subjects wih Resistance Mutations Visit Source: Hatono H, et al. J Acquir Immune Defic Syndr. 2010;54:

22 Virologic Failure with Raltegravir in Initial Regimen Subsequent Therapy Resistance to raltegravir evolves progressively Avoid prolonged failure Integrase genotype may be helpful for 2 nd 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

23 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

24 Questions?