What is the virological support for reduced drug regimens?

What is the virological support for reduced drug regimens? Pr Anne-Genevieve Marcelin Pitié-Salpêtrière Hospital UMR 1136 University Pierre et Marie Curie Paris, France

Disclosure of Personal and Commercial Support & Handling of Bias AG Marcelin has no commercial interests. AG Marcelin has received travel grants, honoraria, and study grants from various pharmaceutical companies including Gilead Sciences, Merck-Sharp & Dohme-Chibret, Janssen- Cilag and ViiV Healthcare. AG Marcelin prepared the content of this presentation using his own material with no commercial input. AG Marcelin may discuss cases and circumstance when drugs are used off label; this is his own personal clinical experience. For the proper use of medications, please review the Product Monographs.

Current recommendations HIV infection is deleterious starting in the very first days following infection No current strategy for HIV cure HIV has to be controlled with life long ART 3-drugs combination is still recommended for all patients starting treatment Recent guidelines provide some recommendations for simplification in virologically suppressed patients

1987 AZT monotherapy B.A Larder et al ; Nature 1993 1994-1995 NRTI dual therapy 1996-1997 2 NRTI + PI B.A Larder et al ; Science 1989

Pressure Drug A Pressure Drugs A + B WT virus virus resistant to drug A virus resistant to drug B virus resistant to drug C virus resistant to drugs A + B Drugs. A + B + C = 0 Prob. 1 virus resistant to drug A 1/10 000 to 100 000 (10-4 to 10-5 ) Prob. 1 virus resistant to drug B 1/10 000 to 100 000 (10-4 to 10-5 ) Prob. 1 virus resistant to drugs A+B 10-4 /10-5 x 10-4 /10-5 = 10-8 to 10-10 Prob. 1 virus resistant to drug C 1/10 000 to 100 000 (10-4 to 10-5 ) Probability 1 virus resistant to drugs A + B + C = 1/10-12 to 10-15 <<< 10 9 to 10 10 of new viruses/day

Do we still need 3 ARV to achieve viral suppression? Patients are initiated at much earlier stages (2010-2013): shift in CD4: 200 to 405 cells/mm 3 HIV VL: 5 to 4.58 log 10 cps/ml Need for evaluation of lighter antiretroviral regimens, i.e. dual or single ARV combinations with potential benefits reduced toxicity better tolerability less resistance class-sparing lower costs Rather than triple therapy for all, the new dogma should become ART and lifelong viral suppression for all

Ideal candidates High antiviral potency High robustness in term of genetic barrier to resistance Favorable pharmacokinetics properties (minimal inter and intra variability)

Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance (1) (2) (3) these immature virions produced in the presence of PIs are incapable of efficiently completing entry (1), reverse transcription (2), and post reverse transcription steps (3) At clinical concentrations, the entry inhibition by PIs is a major component of their overall inhibitory potential PIs act like multiple drugs in one S.Alireza Rabi et al; J.Clin. Invest. 2013

Change from BL in HIV RNA (log 10 ) 50mg QD 400mg BID 50mg QD + RTV 50mg QD 25-150mg QD 900mg BID 750mg QD 200mg QD 100mg BID 400mg BID + RTV 300mg BID 150 mg BID 300mg BID POTENCY: ARTs in MONOTHERAPY INSTI PI 0-0.5-1 -1.5-1.2-1.19-0.52 600mg BID -2-2.5-3 -2.5-1.7-2.03-2.06-1.99 1. Min S. AIDS 2011. 2. DeJesus E. J Acquir Immune Defic Syndr 2006 ; 43:1-5. 3. Markowitz et al. JAIDS Volume 43(5) 15 December 2006 pp 509-515. 4. Gallant JE et al. JAIDS 2017 5. Goebel et al. AIDS 2006, 20:1721 1726. 6. Sankatsing et al. AIDS 2003, 17:2623 2627. 7. Fätkenheuer G, et al. IAS 2007. Abstract WESS202. -1.8-1.7-1.96-1.85-1.6 ** Approved dose for etravirine is 200mg BID 8. Adkins et al. Drugs 1998, 56( 6): 1055-1064 9. Kilby JM. AIDS Res Hum Retroviruses 2002; 18:685-694. 10. Murphy RL. AIDS 2001;15:F1-F9. 11. Fätkenheuer G et al. Nat Med 2005 Nov; 11:1170-1172. 12. Eron JJ, N Engl J Med 1995, 333:1662-1669. -1.80

Clinical trials in naive patients : INI vs EFV and INI vs IP/r INI vs EFV ATV/r DRV/r RAL STARTMRK RAL EFV ACTG A5257 RAL > ATV/r & DRV/r EVG/co GS-US-236-0102 EVG/co EFV GS-US-236-0103 EVG/co ATV/r WAVES EVG/co > ATV/r DTG SINGLE DTG > EFV* ARIA DTG > ATV/r FLAMINGO DTG > DRV/r : Non-inferiority ; > : Superiority ; * DTG/ABC/3TC > EFV/TDF/FTC Références en fin de présentation

Ideal candidates High antiviral potency High robustness in terms of genetic barrier to resistance Favorable pharmacokinetics properties (minimal inter and intra variability)

PI Resistance Rare at VF in First-line Studies of Boosted PIs Study n PI Wk Genotypes Major PI Mutations CASTLE [1] 440 443 ATV/RTV LPV/RTV 96 26 26 1 0 ACTG 5202 [2] 463 465 ATV/RTV 96 83 57 1 0 Study 103 [3] 355 ATV/RTV 144 NR 0 ARTEMIS [4] 343 346 DRV/RTV LPV/RTV 96 31 46 0 0 FLAMINGO [5] 242 DRV/RTV 48 NR 0 ACTG 5257 [6] 605 601 ATV/RTV DRV/RTV 96 75 99 0 0 Among 4303 pts in these trials, only 2 pts developed major PI mutations at initial VF 1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 3. Clumeck N, et al. EACS 2013. Abstract LBPS7/2. 4. Mills A, et al. AIDS. 2009;23:1679-1688. 5. Clotet B, et al. Lancet. 2014;[Epub ahead of print]. 6. Landovitz R, et al. CROI 2014. Abstract 85.

Virologic robustness of DTG Long dissociative half life from integrase (71h) High inhibitory quotient (x19) High virologic potency (-2,46 log in monotherapy) No resistance mutations (INTI and INSTI) in any randomised clinical trials in naive or suppressed patients treated by triple combination Hightower KE, et al. Antimicrob Agents Chemother 2011;5:4552 9 Song I, et al. IWCP 2012. Résumé O07 Elliot E, et al. IWCPHIV 2015. Abstract 13 Min S, et al. AIDS 2011;25:1737 45 Raffi F et al. Lancet Infect Dis 2013;13:927 935 Walmsley S et al. J Acquir Immune Defic Syndr 2015 ViiV data on file (SINGLE 144-week clinical study report) Clotet B et al. Lancet 2014;383:2222 2231 Molina JM et al. Lancet 2015 Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB. Trottier B, et al. ICAAC 2015. Oral presentation Llibre et al. CROI 2017; Seattle, WA. Abstract 2421.

Monotherapy

Virologically suppressed patients PI/r monotherapy:

PI/r monotherapy is possible if Clinical criteria: - High adherence - No previous CNS disorders - Nadir CD4 > 200/mm3 Virological parameters: - Previous long term virologic suppression - > at least 12 months (Guiguet et al ; AIDS 2012) - Low residual viremia - USVL < 1 cp/ml associated with low risk of VF (S Lambert-Niclot et al ; JID 2011) - Low viral DNA before switch - French guidelines: HIV DNA < 200 copies/10⁶ PBMCs and not > 1000 copies/10⁶ PBMCs - No previous failure or resistance - No HBV chronic infection

PI/r monotherapy is possible if Clinical criteria - High adherence - No previous CNS disorders - Nadir CD4 > 200/mm3 Virological - Previous long term virologic suppression > at least 12 months (Guiguet et al ; AIDS 2012) - Low residual viremia USVL < 1 cp/ml associated with low risk of VF (S Lambert-Niclot et al ; JID 2011) - Low viral DNA before switch French guidelines: HIV DNA < 200 copies/10⁶ PBMCs and not > 1000 copies/10⁶ PBMCs - No previous failure or resistance - No HBV chronic infection

Virologically suppressed patients DTG monotherapy: DOMONO: Switch to DTG Monotherapy in Virologically Suppressed Pts Not Sufficient Randomized comparison of switch to DTG 50 mg QD monotherapy vs continued baseline ART for 24 wks in virologically suppressed pts with no previous VF At Wk 24, DTG monotherapy non inferior to continued baseline ART for maintained HIV-1 RNA < 200 c/ml Study d/c early because of high VF rate after 48 wks of DTG monotherapy VF in 8/77 pts with DTG monotherapy vs 3/152 pts on combination ART in concurrent control group (P =.03) Among 6 VF cases with resistance data in DTG monotherapy group, 3/6 developed INSTI resistance (N155H, R263K, S230R, n = 1 each) Wijting I, et al. CROI 2017. Abstract 451LB.

Dual therapy

Virologically suppressed patients PI/r + 3TC DUAL-GESIDA 8014: DRV/r + 3TC Dual ART was non inferior to triple ART (TDF/FTC or ABC/3TC + DRV/r) at Wk 48» No resistance mutations in the 2 dual-therapy patients who experienced virologic failure ANRS 12286/MOBIDIP: after viral suppression with boosted PI plus NRTI in second-line ART, maintenance therapy with boosted PI plus 3TC was associated with a higher rate of success than PI monotherapy, despite the presence of M184V (96%) at first-line treatment failure Pulido F, et al. HIV Glasgow 2016. Abstract O331 Ciaffi L, Lancet HIV 2017, May 28, 2017 (Epub ahead of print)

M184V: reduced replicative capacity => residual activiral effect of 3TC prevents relapse of viral replication in combination with PI/r in patients already suppressed

Virologically suppressed patients INSTI based regimen NNRTI ANRS 163 ETRAL: switch to RAL + ETR was effective in maintaining viral suppression at Wk 48 in 165 patients» 1 pt with VF, VL = 11 607 c/ml confirmed at 18 472 c/ml, RAL S and ETR R : K101E, Y181C and G190A/S (see EACS PS6/4 from Soulie et al.) SWORD: switch from suppressive ART to DTG + RPV was non inferior to continued baseline ART at Wk 48» 1 pt with confirmed criteria for virologic withdrawal at Wk 36 in DTG + RPV arm had K101K/E, no INSTI resistance 3TC LAMIDOL: switch to DTG + 3TC was effective in maintaining viral suppression at Wk 48» no INSTI resistance in 3 pts with virologic failure Llibre JM, et al. CROI 2017. Abstract 44LB. Joly V, et al. CROI 2017. Abstract 458.

ACTG A5353: DTG + 3TC for Treatment-Naive Pts Single-arm phase II study ART-naive pts with HIV-1 RNA 1000 and < 500,000 copies/ml; no RT, INSTI, major PI resistance mutations (N = 120) Baseline: 31% HIV-1 RNA > 100,000 c/ml DTG 50 mg + 3TC 300 mg Primary Endpoint Wk 24 Virologic Outcome at Wk 24, n (%) Baseline HIV-1 RNA, copies/ml > 100,000 (n = 37) 100,000 (n = 83) Total (N = 120) Success* 33 (89) 75 (90) 108 (90) Nonsuccess 3 (8) 2 (2) 5 (4) No data 1 (3) 6 (7) 7 (6) *HIV-1 RNA < 50 copies/ml. n = 3 with PDVF; n = 1 with emergent M184V and R263R/K mixture All 3 pts had DTG levels reflective of suboptimal adherence 1. Taiwo BO, et al. IAS 2017. Abstract MOAB0107LB. 2. ClinicalTrials.gov. NCT02831673. 3. ClinicalTrials.gov. NCT02831764.

Conclusions (1) Triple therapy: remains the gold standard for virologists - No resistance in case of first line VF with PI/r or DTG Drugs with high potency and high genetic barrier to resistance HIV treatment is currently evolving towards individualized therapy - To adjust chronic therapies to each individual 20% of patients are receiving dual therapies in our clinical center - We need to evaluate these strategies

Conclusions (2) Monotherapy - With DTG not recommended - Unacceptable risk of resistance in case of VF - Possible in virologically suppressed patients With PI/r Mainly DRV/r Despite LLV, no emergence of resistance Clinical and virological tools to identify good candidates (UsVL < 1 cp/ml, HIV DNA < 2.3 log and no resistance) Represents only 4% of patients in our clinical center

Conclusions (3) Dual therapy In virologically suppressed: Several options: with PI/r or DTG RT inhibitors are still needed: 3TC or NNRTI (RPV, ETR) 3TC can be substitute to 2 NRTIs even when it shouldn t work Need for more resistance data in case of VF in routine care: risk of resistance higher than with triple therapy? In naïve: Waiting for large clinical trials results: GEMINI 1 & 2 Phase IIII, DTG/3TC vs DTG/TDF/FTC (results expected in 2018) Risk of reactivation when removing 3TC/FTC/TDF in patients with chronic HBV infection

Virology Pitié-Salpêtrière Pr Vincent Calvez Dr Marc Wirden Dr Eve Todesco Dr Cathia Soulie Dr Thuy Nguyen Isabelle Malet Nathalie Desire Saint Antoine Pr L Morand Joubert Dr Sidonie Lambert-Niclot Dr Djeneba Fofana Infectious Diseases Pr Christine Katlama Dr Roland Tubiana Dr Marc-Antoine Valantin Rachid Agher Biostatistics Dr Philippe Flandre Pr Dominique Costagliola Dr Lambert Assoumou Maxime Grude