NORTHWEST AIDS EDUCATION AND TRAINING CENTER Crafting an

NORTHWEST AIDS EDUCATION AND TRAINING CENTER Crafting an ART Regimen for Initiation or Salvage: Are NRTI’s Necessary? Brian R. Wood, MD Assistant Professor of Medicine, University of Washington Medical Director, NW AETC ECHO Last Updated: 1/22/15

NRTI-Sparing Regimens: Outline • • Treatment initiation Switching for maintenance Salvage therapy Future questions and directions

Why Consider NRTI-Sparing Regimens? • NRTI’s are the backbone of first-line and salvage regimens • However, toxicity can be limiting - Tenofovir renal and bone effects - Abacavir hypersensitivity if B*5701(+), ? CV effects - Older NRTI’s many short and long-term side effects • Resistance may preclude use

NRTI SPARING-REGIMENS Data for Use as Initial Therapy

PI-Containing Dual Regimens for Initial Therapy Study NRTISparing Regimen Comparator N Follow-up Efficacy Outcomes and Issues NEAT/ ANRS 143 DRV/r + RAL DRV/r + 2 NRTI’s 805 96 weeks Noninferior More failures and resistance if CD 4 <200 or VL >100 K RADAR DRV/r + RAL DRV/r + 2 NRTI’s 83 48 weeks Inferior More failures and treatment discontinuations ACTG 5262 DRV/r + RAL None 112 96 weeks High rate of failure (26%) High rates of RAL resistance if VL >100 K PROGRESS LPV/r + RAL LPV/r + 2 NRTI’s 206 96 weeks Noninferior Few participants with VL >100 K SPARTAN ATV (300 mg BID) + RAL ATV/r + 2 NRTI’s 94 Stopped at 24 weeks Inferior More failures with resistance and more jaundice NEAT/ANRS 143: Raffi F et al. Lancet. 2014; 384: 1942 -51. RADAR: Cutrell JM et al. PLo. S One. 2014 Aug 29; 9(8): e 106221. ACTG 5262: Taiwo B et al. AIDS. 2011; 13; 25(17): 2113 -22. PROGRESS: Reynes J et al. AIDS Res Hum Retroviruses. 2013 Feb; 29(2): 256 -65. SPARTAN: Kozal MJ et al. HIV Clin Trials. 2012 May-Jun; 13(3): 119 -30.

PI-Containing Dual Regimens for Initial Therapy Study NRTISparing Regimen Comparator N Follow-up Efficacy Outcomes and Issues ACTG 5142 LPV/r + EFV LPV/r + 2 NRTI’s or EFV + 2 NRTI’s 757 112 weeks Non-inferior More resistance, hyperlipidemia MODERN DRV/r + MCV (150 mg daily) DRV/r + 2 NRTI’s 791 Stopped at 48 weeks Inferior More failures, especially if VL >100 K MIDAS DRV/r + MCV (150 mg daily) None 25 96 weeks Failure rate 16. 7% at 48 weeks More failures if VL >100 K A 4001078 ATZ/r + MCV (150 mg daily) ATZ/r + TDF-FTC 121 48 weeks Non-inferior More low-level viremia, more hyperbilirubinemia, not fully powered ACTG 5142: Mugavero MJ et al. J Acquir Immune Defic Syndr. 2011 Nov 1; 58(3): 253 -60. MODERN: Stellbrink HJ et al. 20 th International AIDS Conference; July 2014; Melbourne. Abstract TUAB 0101. MIDAS: Taiwo B et al. 19 th International AIDS Conference: Abstract TUPE 099. A 4001078: Mills A et al. JAIDS. 2013 Feb 1; 62(2): 164 -70.

“NRTI-Lite” Regimens for Initial Therapy Study NRTISparing Regimen Comparator N Follow-up Efficacy Issues GARDEL LPV/r + 3 TC LPV/r + 2 NRTI’s 426 48 weeks Noninferior Comparator NRTI’s mostly AZT & 3 TC ACTG 5303 DRV/r + MVC (150 TDF/FTC mg daily) + FTC 254 Ongoing… GARDEL: Cahn P et al. 14 th European AIDS Conference. Brussels; Sept. 2013. Abstract LBPS 7/6. ACTG 5303: https: //clinicaltrials. gov/ct 2/show/NCT 01400412

NRTI-Sparing or “Lite” Regimens for Initial Therapy: Summary • Studies limited by unusual dosing, outdated comparators, insufficient power, and other issues • Most studies show lower efficacy or more side effects without improving pill burden or dosing frequency • Two trials with the most reassuring results used boosted lopinavir, which is no longer a recommended agent • Need well-designed trials of modern drugs! - ie. boosted darunavir + dolutegravir +/- 3 TC/FTC

NRTI SPARING-REGIMENS Data for Use as Maintenance Therapy

New Data from IAS 2014 Switching to 2 -Drug Regimen for Maintenance Study NRTISparing Regimen Comparator N Follow-up Efficacy SALT ATZ/r + 3 TC ATZ/r + 2 NRTI’s 286 48 weeks Noninferior OLE LPV/r + 3 TC or FTC LPV/r + 2 NRTI’s 239 48 weeks Noninferior HARNESS ATZ/r + RAL ATZ/r + 2 NRTI’s 109 Stopped at 48 weeks Inferior MARCH MVC (150 mg BID) + boosted PI MVC (300 mg BID) + 2 NRTI’s 560 Ongoing… Outcomes and Issues More virological rebound and lowlevel viremia SALT: Perez-Molina JL et al. 20 th International AIDS Conference; July 2014; Melbourne. Abstract LBPE 18. OLE: Gatell JM et al. 20 th International AIDS Conference; July 2014; Melbourne. Abstract LBPE 17. HARNESS: Van Lunzen J et al. 20 th International AIDS Conference; July 2014; Melbourne. Abstract LBPE 19. MARCH: https: //clinicaltrials. gov/ct 2/show/NCT 01384682

NRTI SPARING-REGIMENS Data for Use as Salvage Therapy

NRTI-Sparing Regimens for Salvage Therapy Randomized Trials Study ART History NRTISparing Regimen Comparator N F/u Efficacy Issues OPTIONS PI failure >2 active agents, no agents + NRTI’s 360 48 weeks Noninferior Greater mortality in NRTI arm; only powered to detect 15% non-inferiority SECONDLINE NNRTI failure LPV/r + RAL LPV/r + 541 2 or 3 NRTI’s 48 weeks Noninferior Open-label, genotype optional, included AZT, endpoint VL <200 EARNEST NNRTI failure LPV/r + RAL then LPV/r + NRTI’s 1277 96 weeks Dual therapy noninferior More resistance and less VL suppression with LPV/r monotherapy OPTIONS: Tashima K et al. 20 th CROI. Atlanta, March 2013. Abstract 153 LB. SECOND-LINE: Boyd MA et al. Lancet. 2013 Jun 15; 381(9883): 2091 -9. EARNEST: Paton NI et al. N Engl J Med. 2014 Jul 17; 371(3): 234 -47.

NRTI-Sparing Regimens for Salvage Therapy Observational Studies Study ART History NRTISparing Regimen Comparator N F/u Efficacy Imaz et al. Triple 2011 class failure >2 active agents, no NRTI’s >2 active agents, + NRTI’s 122 48 weeks Non-inferior INROADS Failing or naïve with resistance DRV/r + ETR None 54 48 weeks 100% VL suppressed (failing); 87% (naïve) Nozza et al. 2011 Triple class failure or resistance RAL + ETR None + MVC (all BID) 28 96 weeks 96% VL <50 copies Imaz et al. Triple 2009 class resistance RAL + ETR None + DRV/r (all BID) 32 24 weeks 94% VL<50 copies Imaz et al. J Antimicrob Chemother. 2011 Feb; 66(2): 358 -62. INROADS: Ruane P et al. 7 th IAS Conference. Kuala Lumpur, Malaysia. July 2013. Abstract WEPE 515. Nozza et al. JAIDS. 2011 April; 56(4): e 113 -e 115. Imaz et al. J Acquir Immune Defic Syndr. 2009 Nov 1; 52(3): 382 -6. Outcomes and Issues 75% study completion; 2 acquired ETR resistance

Should Cost Be a Consideration? • VERITAS (Trottier et al, Nov 2014): - 31 subjects with MDR HIV, on >4 ARV’s (w/1 inactive NRTI) - 3 TC or FTC removed in 29 (94%); AZT or TDF in others - 1 or 2 ARV removals mean annual savings of $3319 CDN or $8630 CDN respectively VERITAS: Trottier L et al. J Int AIDS Soc. 2014; 17(4 Suppl 3): 19815.

Future Questions and Directions • Will we worry so much with tenofovir alafenamide (TAF)? • What about dolutegravir? Need data for the following: - Dolutegravir + boosted PI (+/- 3 TC or FTC) - Rilpivirine + boosted darunavir + dolutegravir • How might cabotegravir (GSK-744) or rilpivirine-LA fit in?

NRTI-Sparing Regimens Take Home Points • Most data for initial therapy is limited by design/dosing issues • Dual therapy options should be used only in unique cases and perhaps for maintenance in select patients • Anecdotally, “NRTI-lite” regimens like 3 TC/FTC + boosted PI + integrase seem to work well, but we need data • More advanced HIV disease equates to higher risk of failure • Could consider including NRTI’s for salvage, at least until suppressed, then simplify

Case Question • A patient previously treated with multiple NRTI’s, efavirenz, and boosted lopinavir transfers care to you. He has been off ART and viral load is 9, 400. Prior genotypes show K 103 N, E 138 A, M 184 V, M 41 L, T 215 Y, K 219 Q, and PI mutations (but no darunavir-associated mutations). • He has never taken integrase inhibitors. You plan to restart ART with boosted darunavir, etravirine, and dolutegravir. • Would you add lamivudine (3 TC) or emtricitabine (FTC)? A) Yes, would add indefinitely B) Yes, would add until viral load suppressed then withdraw C) No, would not add