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Mark A Wainberg McGill University AIDS Centre Jewish General Hospital

What if HIV Could not Develop Resistance to a New Integrase Inhibitor when that Compound Is Used in First-Line Therapy?. Mark A Wainberg McGill University AIDS Centre Jewish General Hospital. Disclosures. I have received honoraria from

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Mark A Wainberg McGill University AIDS Centre Jewish General Hospital

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  1. What if HIV Could not Develop Resistance to a New Integrase Inhibitor when that Compound Is Used in First-Line Therapy? Mark A Wainberg McGill University AIDS Centre Jewish General Hospital

  2. Disclosures I have received honoraria from AbbVie, Bristol Myers Squib, Gilead, Janssen,Merck, ViiV

  3. Antiretroviral Drug Approval:1987 - 2014 DTG EVG ETR RAL MVC RPV ENF ATV FTC FPV DRV TPV TDF EFV ABC LPV/r RTV IDV NVP APV NFV DLV 3TC SQV d4T ddC ddI AZT

  4. ART Responses in British Columbia 2000-2008 87% 65% Year N = Gill CID 2010;50:98

  5. 40 100 Deaths 80 30 60 Therapy with a Protease Inhibitor Deaths per 100 Person-Years (% of patient-days) 20 40 Use of protease inhibitors 10 20 0 0 1994 1995 1996 1997 Palella F, et al. NEJM, 1998.

  6. Exemples de transmission de virus multirésistants dans les cas d’une primo-infection par le VIH-1 INTI : Inhibiteurs nucléosidiques de la transcriptase inverseINNTI : Inhibiteurs non nucléosidiques de la transcriptase inverseIP : Inhibiteurs de la protéase Brenner, B. et coll., AIDS, 18(12), le 20 août2004, p. 1653–1660.

  7. ECHO and THRIVE double-blind study designs 48 weeks primary analysis 96 weeks final analysis ECHO (TMC278-C209) RPV 25mg qd + TDF/FTC + EFV placebo qd (N=346) N=690 patients 1:1 EFV 600mg qd + TDF/FTC + RPV placebo qd (N=344) THRIVE (TMC278-C215) RPV 25mg qd + 2 N(t)RTIs* + EFV placebo qd (N=340) N=678 patients 1:1 EFV 600mg qd + 2 N(t)RTIs* + RPV placebo qd (N=338) *Investigator’s choice: TDF/FTC; AZT/3TC; ABC/3TC • RPV was non-inferior to EFV in confirmed response (viral load <50 copies/mL, ITT-TLOVR) at Week 48 (primary objective)1 • RPV had a more favourable safety profile but higher virologic failure rate than EFV1 • RPV is approved in the US as a single-agent tablet2 and a qd fixed-dose, single-tablet regimen with TDF/FTC is under development3 1Cohen CJ, et al. XVIIIth IAC 2010. Abstract THLBB206 2FDA label for EDURANTTM (rilpivirine) tablets. 20113Mathias A, et al. XVIIIth IAC 2010. Abstract LBPE17 ITT = intent-to-treat; TLOVR = time-to-loss of virologic response

  8. Rilpivirine RPV vs EFV

  9. Pooled ECHO and THRIVE: ITT-TLOVR outcome at Week 96 by baseline VL Responders RPV -5.2 (-12, 1.5)§ EFV 4.0 (–1.7, 9.7)§ Patients (%) 70 75 Patients (%) Non responders 84 80 Discontinued due to other reasons† Discontinued due to AE/death VFeff RPVN’=318 EFVN’=353 RPVN’=368 EFVN’=329 >100K ≤100K • Responses by baseline CD4 cell count were (≥200 cells/mm3): RPV 82% vs EFV 79%, (≥50–<200 cells/mm3): RPV 71% vs EFV 75% and (<50 cells/mm3): RPV 56% vs EFV 69%

  10. Pooled ECHO and THRIVE: summary of resistance findings *One VFres occurred after Week 96 in RPV group (E138K, K219E, M184I); †At least one emergent NNRTI RAM (from the NNRTI RAM list)1 or IAS-USA N(t)RTI2 RAM 1Tambuyzer L et al. Antivir Ther 2009;14:103–9 2Johnson VA et al. Top HIV Med 2009;17:138–45

  11. Compensatory effect of E138K on the replication capacity (RC) of M184I/V. • The RC of both E138K and M184I are each decreased by 3-fold compared to wild-type and decreased by 2-fold for M184V. • There is no difference in RC of double mutants E138K/M184I or E138K/M184Vc compared to wild-type .

  12. What is the proper definition of: Genetic barrier for resistance? Number of mutations needed for a minimal level of resistance Number of mutations needed for resistance > 10-fold Time to development of clinically relevant resistance Duration of exposure to drug in order for resistance to occur Number of viral replicative cycles required to overcome inhibition by a drug. All of the above

  13. Number of mutations needed for a minimal level of resistance or resistance > 10-fold ClassDrugMutationFold-change NNRTI Nevirapine Y181C >100 Efavirenz K103N >100 N(t)RTI 3TC M184V >100 Tenofovir K65R ≈ 3-fold Abacavir L74V 3-5 fold PI Darunavir >10 mutations 5-20 fold Lopinavir >8 mutations 5-20 fold

  14. Time to development of clinically relevant resistance 1. Single dose NVP. Weeks? 2. Triple therapy. Only in cases of adherence? 3. With PIs, resistance based on mutations in PR is rare, even in cases of viral load rebound. What about cleavage site mutations in gag? Monitoring of cleavage site mutations is uncommon. 4. Oftentimes, compensatory mutations serve to increase levels of resistance while simultaneously restoring viral fitness that may have been impaired by a primary mutation, e.g. (a) zidovudine, the various TAM pathways; (b) the 148/140 mutational pathway for raltegravir and elvitegravir.

  15. 5. Does the concept of genetic barrier apply to transmitted resistance? E.g. K103N, TAMs, M184V (-the latter is commonly deselected after transmission).

  16. The new era of integrase inhibitors: potent and well-tolerated drugs

  17. FLAMINGO (ING114915) Study Design Open-label randomized phase Extension phase HIV+ ART-naiveVL ≥1,000 c/mL Stratified by screening plasma HIV-1 RNA (≤ vs >100,000 c/mL) and background dual NRTI (ABC/3TC or TDF/FTC*) DTG 50 mg QD + 2 NRTIs DTG + ART DRV/r 800 mg/100 mg QD + 2 NRTIs Randomization Week 48 analysis Week 96 analysis Primary endpoint: proportion with HIV-1 RNA <50 c/mL at Week 48, FDA Snapshot analysis, -12% non-inferiority (NI) margin Secondary endpoints: antiviral activity, safety, tolerability, health outcomes and viral resistance *Investigator selected backbone of choice Clotet et al. EACS 2013; Brussels, Belgium. Abstract LBPS4/6.

  18. Proportion (95% CI) of Individuals With HIV-1 RNA <50 c/mL Over Time – Snapshot DTG: 90% DRV/r: 83% 95% CI for differencea FavoursDRV/r FavoursDTG Proportion (%) 0.9 7.1 13.2 -20% -12% 0 20% BL 4 8 12 16 24 36 48 Test for superiority: P=0.025 Week Results were confirmed in per protocol analysis: 91% DTG versus 84% DRV/r, ∆ (CI): 7.4 (1.4 - 13.3) Clotet et al. EACS 2013; Brussels, Belgium. Abstract LBPS4/6.

  19. Resistance to INSTIs in clinical trials in treatment-naïve patients RALTEGRAVIR Cooper et al., NEJM, 2008 Sichtig et al, JAC, 2009 Canducci et al, AIDS, 2009 Hatano et al, JAIDS, 2010 ELVITEGRAVIR Sax et al, Lancet, 2012 DeJesus et al, Lancet, 2012 DOLUTEGRAVIR vanLunzen et al., Lancet Infect. Dis., 2012

  20. Major resistance pathways against INSTIs(clinical and tissue culture data) Quashie et al., Curr. Opin. Infect. Diseases, in press

  21. SAILING • CROI 2013. A study in which Dolutegravir was shown to be superior to Raltegravir in treatment-experienced integrase inhibitor-naïve subjects. • The R263K mutation was present in two individuals who either rebounded or did not achieve virologic suppression to <50 c/ml.

  22. Disclaimer The following hypothesis has been formulated by our research group and is not necessarily subscribed to by either ViiV Healthcare, Inc. or GlaxoSmithKline, Inc.

  23. Subtype-specific mutations selected in vitro with dolutegravir Quashie, Mesplède et al., Journal of Virology, 2012

  24. The R263K mutation confers low-level resistance to dolutegravir in cell culture *Methodological differences (EC50 for wild-type ≈1-6nM) Quashie, Mesplède et al., Journal of Virology, 2012

  25. InI Dissociation from WT IN-DNA Complex at 37°C DTG RAL EVG 1.0 0.8 0.6 Relative binding 0.4 0.2 0.0 0 10 20 30 40 50 60 Time (h) • DTG dissociated more slowly from a WT IN-DNA complex at 37°C compared with RAL and EVG • DTG dissociation was eight times longer than RAL and 26 times slower than EVG Adapted from Hightower KE, et al. Antimicrob Agents Chemother 2011;5:4552–9 Koff , dissociation rate; t1/2h, half-life in hours

  26. The R263K mutation decreases integrase activity in cell-free assays Quashie, Mesplède et al., Journal of Virology, 2012

  27. The addition of H51Y to R263K further decreases IN strand transfer activity A B

  28. The addition of H51Y to R263K further decreases HIV-1 infectivity

  29. R263K and H51Y/R263K affect integrase structure Effect of the H51Y and R263K mutations on integrase structure. Effect of residues at position 51 and 263 on local side-chain electrostatic interactions and side-chain mobility of: A. INwt (turquoise backbone); B. INH51Y (purple backbone); C. INR263K (salmon backbone) and D. INH51Y/R263K (Dark green backbone). Mesplède et al. Retrovirology 2013

  30. No compensatory mutations in regard to DTG resistance and viral fitness have developed over more than four years in culture.

  31. Selection of HIV-1 containing R263K with RAL and EVG

  32. Replication Capacity of HIV Containing Various Combinations of INSTI Resistance Mutations

  33. Clinical resistance has occurred in regard to every HIV drug developed until now and therefore must continue to occur for all future medications as well.

  34. Approaches Being Used to Purge HIV Reservoirs Histonedeacetylase (HDAC) inhibitors Farnesyltransferase inhibitors Antibody and immunological approaches Others

  35. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy NM Archin, AL Liberty, AD Kashuba, SK Choudhary, JD Kuruc, AM Crooks, DC Parker, EM Anderson, MF Kearney, MC Strain, DD Richman, MG Hudgens, RJ Bosch, JM Coffin, JJ Eron, DJ Hazuda, DM Margolis Nature 487, 482-485 (26 July 2012) doi: 10.1038/nature11286

  36. Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys JB Whitney, AL Hill, S Sanisetty, P Penaloza-MacMaster, J Liu, M Setty, L Parenteau, C Cabral, J Shields, S Blackmore, JY Smith, AL Brinkman, LE Peter, SI Mathew, KM Smith, EN Borducchi, DIS Rosenbloom, MG Lewis, J Hattersley, B Li, J Hesselgesser, R Geleziunas, ML Robb, JH Kim, NL Michael, DH Barouch Nature512, 74-77 (7 August 2014) doi: 10.1038/nature13594

  37. At the very least, a drug that does not easily select for drug resistance should be intolerant of ongoing HIV transmission so long as patients remain adherent to therapy.

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