State of the ART: Integrase Inhibitor Resistance Jeroen van Kampen Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands j.vankampen@erasmusmc.nl

disclosures Jeroen van Kampen Companies/funders Sponsoring or research fee Inventor on patent “Methods for determining antibiotic resistance in microorganisms” (15197806.1 – 1408 / 3023503) EU project EHVA (#681032) Erasmus MC (patent holder), Bruker Daltonics (licence)

HIV life cycle Volberding et al., Lancet, 2010

HIV DNA integration Adapted by Clavel from Craigie & Bushman, Cold Spring Harbor Perspectives in Medicine, 2012

integrase strand transfer inhibitors (INSTI) Poonvaganam et al., RSC Adv, 2014; Thierry et al., Front Microbiol, 2017

First generation INSTI raltegravir (RAL) elvitegravir (EVG)

Resistance to first generation INSTI Raltegravir FDA drug label 40% (4/10) in ART naive 68% (76/112) in ART experienced Clinical practice 34% (97/285) 26% in ART naive (8/31) Elvitegravir 71.8% (191/266) ± 40% (14/35) in ART naive 43% (52/122) 38% in ART naive (6/16) RAL FDA label naive STARTMRK studies RAL FDA label experienced BENCHMARK studies Clinical practice: French ANRS network. Observational multi-center study. N = 513 (VF 2x > 50 c/mL). ANRS interpretation algorithm EVG FDA drug label naive 102 & 103 studies. Minimum 14/35 and max 18/35 with EVG-RAM. Isentress FDA drug label.; Marcelin et al., presentation # O_#03, European HIV clinical forum, Milan, Italy, 2017.; Stribild FDA drug label

RAL resistance pathways Spach et al., national HIV curriculum, 2017

EVG resistance pathways www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203093Orig1s000MicroR.pdf

Cross-resistance RAL and EVG Gerretti ed, antiretroviral resistance in clinical practice; Quashie et al., Curr Opin infect Dis, 2013

Raltegravir – accumulation of resistance mutations Hatano et al., J Acquir Immune Defic Syndr, 2010; Spach et al., national HIV curriculum, 2017

Elvitegravir – accumulation of resistance mutations Winters et al., plos one, 2012

Accumulation of resistance mutations over time Canducci et al., J Infect Dis, 2011

Second generation INSTI dolutegravir (DTG) bictegravir (BIC) cabotegravir (CAB)

Resistance to second generation INSTI DTG FDA drug label 0% (0/9) in ART naive 21% (6/28) in ART experienced Clinical practice 0% (0/6) in ART naive 15% (16/106) for DTG o.d. 6% (6/106) for DTG b.i.d. DTG dual therapy ? DTG monotherapy 40% (4/10) 82% (9/11) BIC 0% (0/8) in ART naive 0% (0/1) in ART experienced CAB Tivicay FDA drug label.; Marcelin et al., presentation # O_#03, European HIV clinical forum, Milan, Italy, 2017.; Wijting et al., J Infect Dis, 2018.; Blanco et al., CROI 2017, abstract 42.; Biktarvy FDA drug label

Genetic barrier to resistance Clutter et al., Infect Genet Evol, 2016

Cross-resistance RAL/EVG and DTG Quashie et al., Curr Opin infect Dis, 2013

VIKING-3 study DTG b.i.d. in RAL/EVG resistant HIV infection Resistance against RAL/EVG + ≥ 2 drug classes 1 fully active drug in optimized backbone regimen HIV-RNA < 50 c/mL at week 24 No Q148 100/126 (79%) Q148 + 1 mutation 21/36 (58%) Q148 + ≥ 2 mutations 5/21 (24%) Castagna et al., J Infect Dis, 2014

Resistance: 1st generation vs 2nd generation INSTI Smith et al., retrovirology, 2018

Resistance: 1st generation vs 2nd generation INSTI Smith et al., retrovirology, 2018

INSTI resistance – are we looking in the wrong place?

INSTI resistance outside integrase 3' polypurine tract (PPT) In vitro selection experiments under high DTG concentrations   3' polypurine tract (PPT) HXB2_ref A G 9053 Lai* C T - Malet et al., mBio, 2017

Wijting et al., J Infect Dis, 2018 4 6 10 1 2 3 9 8 5 7 DOMONO study main pilot adherence > 95% DTG level at VF 1.29 (+14h) 2.00 (+19h) 5.31 2.59 (+16h) 2.96 (+22h) 1.00 (+24h) 0.86 1.44 0.70 (+13h) 2.15 (+9h) INSTI-RAM no - S230R E92Q + N155H R263K N155H Wijting et al., J Infect Dis, 2018

First patient failing on INSTI with development of mutations in 3’-PPT No INSTI-RAMs detected!   3' polypurine tract (PPT) HXB2_ref A G 9053 Lai* C T - Pat 10 Wijting et al., J Infect Dis, 2018

Summary First generation INSTI Raltegravir, elvitegravir Resistance relatively common upon virologic failure Cross resistance between RAL and EVG Second generation INSTI Dolutegravir, bictegravir, cabotegravir Resistance relatively uncommon upon virologic failure But not with monotherapy! Activity against RAL/EVG resistant HIV isolates Q148 + additional mutations poor response Resistance outside integrase Resistance via 3’-polypurine tract Role in vivo to be determined

Factors associated with resistance Lepik et al., aids, 2017