1. N ORTHWEST A IDS E DUCATION AND T RAINING C ENTER 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

4. 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

5. Data for Use as Initial Therapy NRTI S PARING -R EGIMENS

6. PI-Containing Dual Regimens for Initial Therapy NEAT/ANRS143: Raffi F et al. Lancet. 2014;384:1942-51. RADAR: Cutrell JM et al. PLoS One. 2014 Aug 29;9(8):e106221. 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.

7. PI-Containing Dual Regimens for Initial Therapy ACTG 5142: Mugavero MJ et al. J Acquir Immune Defic Syndr. 2011 Nov 1;58(3):253-60. 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. A4001078: Mills A et al. JAIDS. 2013 Feb 1;62(2):164-70.

8. “NRTI-Lite” Regimens for Initial Therapy GARDEL: Cahn P et al. 14th European AIDS Conference. Brussels; Sept. 2013. Abstract LBPS7/6. ACTG 5303: https://clinicaltrials.gov/ct2/show/NCT01400412

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 NRTI-Sparing or “Lite” Regimens for Initial Therapy: Summary Studies limited by unusual dosing, outdated comparators, insufficient power, and other issues Most studies show lower efficacy or more side effects without improving pill burden or dosing frequency Two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. Data for Use as Maintenance Therapy NRTI S PARING -R EGIMENS

11. New Data from IAS 2014 Switching to 2-Drug Regimen for Maintenance 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: https://clinicaltrials.gov/ct2/show/NCT01384682

12. Data for Use as Salvage Therapy NRTI S PARING -R EGIMENS

13. NRTI-Sparing Regimens for Salvage Therapy Randomized Trials OPTIONS: Tashima K et al. 20th CROI. Atlanta, March 2013. Abstract 153LB. 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.

14. NRTI-Sparing Regimens for Salvage Therapy Observational Studies 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 WEPE515. Nozza et al. JAIDS. 2011 April;56(4):e113-e115. Imaz et al. J Acquir Immune Defic Syndr. 2009 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  mean annual savings of $3319 CDN or $8630 CDN respectively VERITAS: Trottier L et al. J Int AIDS Soc. 2014; 17(4Suppl 3): 19815.

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