1. State of the ART: Integrase Inhibitor Resistance
Jeroen van Kampen
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands

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

3. HIV life cycle
Volberding et al., Lancet, 2010

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

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

6. First generation INSTI
raltegravir (RAL)
elvitegravir (EVG)

7. 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

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

9. EVG resistance pathways

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

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

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

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

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

15. 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

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

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

18. 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%)
Q mutation
21/36 (58%)
Q148 + ≥ 2 mutations
5/21 (24%)
Castagna et al., J Infect Dis, 2014

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

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

21. INSTI resistance – are we looking in the wrong place?

22. 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

23. Wijting et al., J Infect Dis, 20184 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

24. 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

25. 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

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