Crafting an ART Regimen for Initiation or Salvage: Are NRTI s Necessary?

Transcription

1 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

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

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

5 NRTI SPARING-REGIMENS Data for Use as Initial Therapy

6 PI-Containing Dual Regimens for Initial Therapy Study NRTI- Sparing Regimen Comparator N Follow-up Efficacy Outcomes and Issues NEAT/ ANRS 143 DRV/r + RAL DRV/r weeks Noninferior More failures and resistance if CD4 <200 or VL >100K RADAR DRV/r + RAL ACTG 5262 DRV/r + RAL PROGRESS LPV/r + RAL SPARTAN ATV (300 mg BID) + RAL DRV/r weeks Inferior More failures and treatment discontinuations None weeks High rate of failure (26%) LPV/r + ATV/r weeks Noninferior 94 Stopped at 24 weeks Inferior High rates of RAL resistance if VL >100K Few participants with VL >100K More failures with resistance and more jaundice NEAT/ANRS143: Raffi F et al. Lancet. 2014;384: RADAR: Cutrell JM et al. PLoS One Aug 29;9(8):e ACTG 5262: Taiwo B et al. AIDS. 2011;13;25(17): PROGRESS: Reynes J et al. AIDS Res Hum Retroviruses Feb;29(2): SPARTAN: Kozal MJ et al. HIV Clin Trials May-Jun;13(3):

7 PI-Containing Dual Regimens for Initial Therapy Study NRTI- Sparing Regimen Comparator N Follow-up Efficacy Outcomes and Issues ACTG 5142 LPV/r + EFV MODERN DRV/r + MCV (150 mg daily) LPV/r + or EFV + DRV/r weeks Non-inferior More resistance, hyperlipidemia 791 Stopped at 48 weeks Inferior More failures, especially if VL >100K MIDAS DRV/r + MCV (150 mg daily) None weeks Failure rate 16.7% at 48 weeks More failures if VL >100K A ATZ/r + MCV (150 mg daily) ATZ/r + TDF-FTC weeks Non-inferior More low-level viremia, more hyperbilirubinemia, not fully powered ACTG 5142: Mugavero MJ et al. J Acquir Immune Defic Syndr Nov 1;58(3): MODERN: Stellbrink HJ et al. 20th International AIDS Conference; July 2014; Melbourne. Abstract TUAB0101. MIDAS: Taiwo B et al. 19th International AIDS Conference: Abstract TUPE099. A : Mills A et al. JAIDS Feb 1;62(2):

8 NRTI-Lite Regimens for Initial Therapy Study NRTI- Sparing Regimen Comparator N Follow-up Efficacy Issues GARDEL LPV/r + 3TC LPV/r weeks Noninferior Comparator NRTI s mostly AZT & 3TC ACTG 5303 DRV/r + MVC (150 mg daily) + FTC DRV/r + TDF/FTC 254 Ongoing GARDEL: Cahn P et al. 14th European AIDS Conference. Brussels; Sept Abstract LBPS7/6. ACTG 5303: clinicaltrials.gov/ct2/show/nct

9 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 +/- 3TC/FTC

10 NRTI SPARING-REGIMENS Data for Use as Maintenance Therapy

11 New Data from IAS 2014 Switching to 2-Drug Regimen for Maintenance Study NRTI- Sparing Regimen Comparator N Follow-up Efficacy Outcomes and Issues SALT ATZ/r + 3TC ATZ/r weeks Noninferior OLE LPV/r + 3TC or FTC LPV/r weeks Noninferior HARNESS ATZ/r + RAL ATZ/r Stopped at 48 weeks Inferior More virological rebound and lowlevel viremia MARCH MVC (150 mg BID) + boosted PI MVC (300 mg BID) Ongoing SALT: Perez-Molina JL et al. 20 th International AIDS Conference; July 2014; Melbourne. Abstract LBPE 18. OLE: Gatell JM et al. 20th International AIDS Conference; July 2014; Melbourne. Abstract LBPE17. HARNESS: Van Lunzen J et al. 20th International AIDS Conference; July 2014; Melbourne. Abstract LBPE19. MARCH:

12 NRTI SPARING-REGIMENS Data for Use as Salvage Therapy

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

14 NRTI-Sparing Regimens for Salvage Therapy Observational Studies Study ART History NRTI- Sparing Regimen Comparator N F/u Efficacy Outcomes and Issues Imaz et al Tripleclass failure >2 active agents, no NRTI s >2 active agents, + NRTI s weeks Non-inferior INROADS Failing or naïve with resistance DRV/r + ETR None weeks 100% VL suppressed (failing); 87% (naïve) 75% study completion; 2 acquired ETR resistance Nozza et al Triple class failure or resistance RAL + ETR + MVC (all BID) None weeks 96% VL <50 copies Imaz et al Triple class resistance RAL + ETR + DRV/r (all BID) None weeks 94% VL<50 copies Imaz et al. J Antimicrob Chemother Feb;66(2): INROADS: Ruane P et al. 7 th IAS Conference. Kuala Lumpur, Malaysia. July Abstract WEPE515. Nozza et al. JAIDS April;56(4):e113-e115. Imaz et al. J Acquir Immune Defic Syndr Nov 1;52(3):382-6.

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

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

17 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 3TC/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

18 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 K103N, E138A, M184V, M41L, T215Y, K219Q, 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 (3TC) or emtricitabine (FTC)? A) Yes, would add indefinitely B) Yes, would add until viral load suppressed then withdraw C) No, would not add