Debating view on less ART. Strategies under evaluation

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1 Debating view on less ART Strategies under evaluation Andrea De Luca Dipartimento Biotecnologie Mediche Università di Siena Department of Infectious Diseases, Siena University Hospital, Italy

2 Conflicts of interest Research grants from: ViiV Healthcare Gilead (Fellowship Program) Merck, Sharp and Dohme Paid consultancies: ViiV Healthcare Gilead Sciences Merck, Sharp and Dohme Janssen Bristol-Myers Squibb

3 Outline Regimens with reduced number of drugs Use in clinical practice Evidence from studies First-line Switch in virosuppressed individuals

4 10% 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% Proportion of mono/dual PI therapies according to calendar period of starting for 2017, first 6 months 0.8% 1.7% 5.2% 3.2% 6.4% 4.2% 8.9% 1.7% Dual Mono June 2017 Report

5 Most used DRV-containing mono/dual therapies DRV/r DRV/r,RAL 3TC,DRV/r ETV,DRV/r DRV/r,DGV DRV,cob DRV/r,MRV 3TC,DRV,cob other Most used ATV-containing mono/dual therapies TC,ATV/r ATV/r ATV/r,RAL ATV,RAL other June 2017 Report

6 DGV-containing mono/dual therapies according to calendar period TC,DGV DRV/r,DGV RPV,DGV DRV,DGV,cob ATV,DGV other June 2017 Report

7 June 2017 Report 100% 90% 80% 70% Proportion of patients with a VL<=80 copies/ml at 12 months from starting their first ART regimen by calendar year of initiation 85.5% 88.8% 90.5% 88.9% 88.1% 89.9% 91.2% 94.3% 95.4% 95.7% 83.1% 75.0% 78.1% 80.5% 77.1% 60% 50% 40% 30% 20% 10% 58.1% 52.5% 43.6% 38.3% 17.0% 0%

8 3.7% 0.50% 4.4% 7.8% 4.42% 6.2% 7.3% 13.0% 9.7% 16.7% 20.6% 15.56% 8.7% 16.5% 11.5% 11.93% 9.2% 18.9% 11.2% 7.91% 5.2% 6.8% 25.7% 22.1% 21.4% 21.22% 21.8% 25.24% 40.9% 36.4% 44.9% 51.4% 57.1% 52.7% 61.2% 70% Reasons for stopping at least one drug of the first ART regimen within 1 year, according to calendar period of starting N = therapy interruptions per period 60% 50% 40% 30% 20% 10% 0% (N=602) (N=294) (N=257) (N=218) (N=455) (N=735) (N=206) FAILURE OTHER PATIENT'S DECISION SIMPLIFICATION TOXICITY for 2017, first 6 months June 2017 Report

9 Monotherapies? PI/r monotherapies Inferior to triple, but very rare resistance selection Reinduction + 2NA works DRV/r more solid data: inferior with nadir CD4<200 DTG monotherapy: catastrophe Inferior AND resistance selection How to throw away the most precious ARV class

10 % HIV-RNA <200 c/ml DOMONO DTG as Maintenance Monotherapy For HIV DOMONO is a multicenter randomised non-inferiority trial comparing 96 patients on DTG 50mg QD monotherapy vs cart 0 Viral Suppression at W48 On-Treatment Analysis p= % 98% DTG Mono (N=96) cart (N=152) Pt Characteristics of Virologic Failures on DTG Monotherapy* BL 3 rd agent (with F/TDF) Timing of Failure HIV-RNA at Failure (c/ml) Integrase Sequence at Failure 1 RPV W4 71,600 No RAMs 2 EFV W Not successful 3 RPV W30 3,510 No RAMs 4 RPV W30 1,570 S230R 5 DTG W36 1,440 Not successful 6 RPV W48 4,990 No RAMs 7 NVP W60 3,470 R263K 8 NVP W72 4,180 N155H * All CD4 T-cell nadir 210 cellsmm 3 and >95% adherence (according to clinician) Study prematurely discontinuation due to predefined stopping rule (emergent INSTI resistance) Wijting I, et al. CROI Seattle, WA. Poster #451LB DTG monotherapy efficacy was inferior by Week 48

11 REDOMO: Pathways of Resistance in Subjects Failing DTG Monotherapy Outcomes in Patients Failing DTG Monotherapy after Switch International, multi-cohort, retrospective study characterizing resistance of subjects who switched to DTG monotherapy 50 mg QD (n=122) Monotherapy (N=122) Virologic Failures (%) Blanco JL, et al. CROI Seattle, WA. Oral #42 Bi / Tri-therapy (N=1,082) 9% (n=11) 6% (n=64) 11 subjects in monotherapy arm experienced virologic failures 45% - first INSTI 64% - 95% adherence 72% - 3 years virologic suppressed prior to switch Resistance Selection (%) 82% Monotherapy Bi / Tri-therapy High rate of genotypic resistance selection after DTG monotherapy failure Summary of available studies: InSTI resistance in 15 of 20 9/11 0% Median time from VF until genotypic resistance testing: 5 weeks (IQR: 3-14) DTG monotherapy VFs led to different mutation pathways (92Q,118R,148X and 155H)

12 Less toxic than dual? Why mono? With 3TC/FTC no/minimal added toxicity Less resistance selection (with PI/r) More resistance selection to 3TC/FTC or other classes?

13 Dual therapies in naives Study regimen control n Efficacy outcome Benefits/Harms Gardel LPV/r+3TC LPV/r+2NA 416 Non-inferior (but comparator suboptimal) Less AE, no resistance PADDLE DTG+3TC no 20 18/20 <50 cps at 48w 1 suicide, 1PDVF resuppressed (no change) ACTG A5353 DTG+3TC no % VL>100K. 90% VS. 3 PDVF (1 with M184V and R263R/K) ANDES DRV/r+3TC DRV/r+TVD w: VL<400 in 95% vs 97% 24w VL>100K all <400 GEMINI DTG+3TC DTG+TVD 700 ONGOING Modern DRV/r+MVC QD DRV/r+TVD 804 Inferior Bone NEAT001 DRV/r+RAL DRV/r+TVD 805 Non-inferior, inferior with CD4<200 or VL>100K Bone, egfr/insti-r selection

14 ANDES: DRV/RTV + 3TC vs DRV/RTV + 3TC/TDF for ART-Naive Pts Randomized, open-label phase IV study in Argentina Interim Analysis Wk 24 Primary Endpoint Wk 48 ART-naive pts with HIV-1 RNA > 1000 copies/ml (N = 145) Baseline: 24% HIV-1 RNA > 100,000 copies/ml HIV-1 RNA < 400 c/ml (ITT) at Wk 24, n/n (%) DRV/RTV + 3TC DRV/RTV + 3TC/TDF Overall 71/75 (95) 68/70 (97) BL HIV-1 RNA > 100,000 copies/ml 20/20 (100) 15/15 (100) 1 virologic failure with DRV/RTV + 3TC/TDF DRV/RTV + 3TC QD (n = 75) DRV/RTV + 3TC/TDF QD (n = 70) Dosing: DRV/RTV, 800/100 mg; 3TC, 300 mg; 3TC/TDF, 300/300 mg. Sued O, et al. IAS Abstract MOAB0106LB. Slide credit: clinicaloptions.com

15 HIV-1 RNA (copies/ml) ACTG A5353: HIV-1 RNA Levels and DTG Concentration in Pts Experiencing PDVF Pt 1 BL HIV-1 RNA > 100,000 copies/ml Pt 2 BL HIV-1 RNA 100,000 copies/ml Off DTG Pt 3 BL HIV-1 RNA 100,000 copies/ml Off DTG 1,000, ,000 10, Study Wk None ,000, ,000 10, None M184V M184V R263RK Study Wk ,000, ,000 10, Study Wk V DTG Concentration (ng/ml) HIV-1 RNA (copies/ml) DTG concentration (ng/ml) HIV-1 RNA < limit of detection No detectable DTG Taiwo BO, et al. IAS Abstract MOAB0107LB. Reproduced with permission. Slide credit: clinicaloptions.com

16 Dual RCT in treatment naive: unsuccessful studies DRV/r + MVC inferior to 2NA + DRV/r Well powered ATV/r + MVC inferior to 2NA + ATV/r Small, limited power ATV/r + RAL inferior to ATV/r + 2NA More jaundice, InSTI resistance selection

17 Study Maintenance dual ART: completed prospective trials Previous regimen Study regimen control n Main Efficacy outcome Benefits/Harms ATLAS-M ATV/r+2NA ATV/r+3TC ATV/r+2NA 266 Non-inferior (superior) egfr, bone, AE/lipids SALT Any triple ATV/r+3TC ATV/r+2NA 273 Non-inferior Less AE/lipids OLE LPV/r+2NA LPV/r+3TC LPV/r+2NA 250 Non-inferior No/lipids DUAL DRV/r+2NA DRV/r+3TC DRV/r+2NA 257 Non-inferior MOBIDIP bpi+2na bpi+3tc bpi 265 Dual>mono (VF 48w 3% vs 24.8%) All had previous M184V PROBE PI/r+2NA DRV/r+RPV continue 60 Non-Inferior Bone, immune activation/lipids Multineka LPV/r+2NA LPV/r+NVP LPV/r+2NA 67 Non-inferior GUSTA Any triple DRV/r+MVC qd cont 133 Inferior AE, Bone, AP MARCH PI/r+2NA PI/r+MVC bid 2NRTI+MVC bid cont 395 PI/r+MVC inferior

18 Maintenance dual ART: completed prospective trials Study Previous regimen Study regimen control n Main Efficacy outcome Benefits/Harms LATTE CAB+2NA CAB+RPV IM EFV+2NA 243 Non-inferior LATTE-2 CAB (oral)+abc/3t C CAB+RPV IM q4w or q8w CAB (oral)+abc/ 3TC 309 Non-inferior Patients satisfaction/isr SWORD Any triple DTG+RPV continue 1024 Non-inferior Improved BMD and bone turnover markers SPARE LPV+TVD DRV/r+RAL LPV+TVD 58 egfr urinary b2m improved Harness Any triple ATV/r+RAL ATV/r+2NA 109 Inferior KITE 2NA+X LPV/r+RAL continue 60 Non-inferior no/lipids ANRS 167 LAMIDOL DOLULAM Triple (81% bpi, 26% RAL) 2NA+X DTG+3TC no % success w48 (1 PDVF) Some excluded after induction (VF, tox) DTG+3TC no 27 2 years: no VF 63% had historical RNA or DNA with M184I/V

19 ATV/r+3TC: ATLAS-M 96 weeks

20 Efficacy endpoint analyses at 96 weeks 12% (95% CI 1.2; 22.8) 12.8% (95% CI 1.9; 23.7) 13.5% (95% CI 2.7; 24.3) 14.3% (95% CI 3.4; 25.2)

21 Causes of treatment failure ATV/rit+3TC N=133 ATV/rit+2 NRTIs N=133 Any cause 30 (22.6) 46 (34.6) Virological Failure 2 (1.5)* 9 (6.8) Adverse events (potentially treatment-related) i 7 (5.3) 11 (8.3) Adverse events (not treatment related) ii 3 (2.3) 5 (3.8) Withdrawal of consent 6 (4.5) 9 (6.8) Loss to follow up 10 (7.5) 7 (5.3) Other 2 (1.5) 5 (3.8) Values are expressed as n (%) * One VF at baseline, before treatment simplification. p Notes: i. DT: skin rash (w4), renal colic (w26 and w49), biliary colic (w60), pancreatitis (w62), hypertriglyceridemia (w72), creatinine increase (w75); TT: creatinine increase (w3 and w7), osteopenia (w16), renal colic (w24, w60, w63, w77, w80), drug nephropathy (w43), proteinuria (w84), hyperbilirubinemia (w84). ii. DT: sudden death (w10 and w78, suspect cardiac events), thyroid carcinoma (w24); TT: spinal disc herniation (w3), pneumonia (w12), abdominal cancer (w48), creatinine increase (w60), lung cancer (w72).

22 Virological failures ID Visit HIV-RNA (cp/ml) CD4 (cells/µl) Comments Dual therapy arm 40 BL VF at BL, before treatment simplification. GRT: no resistance. 164 W Triple therapy arm 85 W No subsequent data, lost to follow-up. 247 W VF with low VL (64 and 248 cp/ml); after re-intensification with TDF, subsequent VL 83 cp/ml then <40 cp/ml. GRT: no resistance. Treatment change to elvitegravir/cobicistat/ tenofovir/emtricitabine with virological suppression. GRT PR: 58E. 137 W VL <50 cp/ml without treatment change. GRT: no resistance. 168 W VL <50 cp/ml without treatment change. GRT: no resistance. 23 W VL <50 cp/ml without treatment change. GRT: no resistance. 107 W Subsequently lost to follow up. GRT PR: no resistance. 174 W w w No subsequent data, lost to follow-up. Subsequent follow up not available. GRT PR: no resistance, RT: 101Q, 138A, 179I (intermediate R to ETR, RPV). VF with low VL (55 and 78 cp/ml); treatment change to abacavir/lamivudine+dolutegravir with virological suppression. GRT PR: no resistance RT:215S.

23 Evolution of renal function

24 Bone outcomes at 96 weeks Changes in BMD at 96W (%) Dual arm TT arm Lumbar Spine Total Hip Femoral neck n=73 DT arm: 41 TT arm: 32 p= ns p= ns p= Bone turnover biomarkers (%) Dual arm TT arm p= ns p= ns p= ns p= ns PTH Vitamin D Osteocalcin FAO

25 DUAL-GESIDA 8014: Dual DRV/RTV + 3TC vs Triple DRV/RTV + FTC/TDF or ABC/3TC Randomized, multicenter, open-label, phase IV noninferiority trial Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 48 (ITT-e, FDA snapshot analysis) Pts with HIV-1 RNA < 50 copies/ml for > 6 mos; on triple therapy* 2 mos; HBsAg negative (N = 257) Stratified by baseline NRTI Pulido F, et al. HIV Glasgow Abstract O331. Switch to DRV/RTV + 3TC QD (n = 129) Continue Previous Triple Therapy* (n = 128) *Previous triple therapy regimens: DRV/RTV + FTC/TDF or DRV/RTV + ABC/3TC. Wk 48 Primary endpoint

26 Sensitivity analysis Proportion ofpatients with HIV viral load <50 copies/ml (%) Difference (%) IC 95% DUAL TRIPLE 100% 89% 93% 87% 89% 89% 93% 97% 98% 80% 60% 40% 20% 0% ITT-e (snapshot) ITT (snapshot) Per-Protocol (snapshot) Observed data Observed data: excluding non-virological reasons for failure. DUAL-GESIDA 8014-RIS EST-45 study: 48 weeks results 28

27 Resistance testing (attempted in all rebounds with viral loads > 400 HIV-RNA copies/ml) GROUP Week HIV-RNA 50 c/ml week 48 (SNAPSHOT) 1 st viral load 2 nd viral load Genotype Mutations DUAL Baseline Yes Yes None DUAL 24 Yes Failed DUAL 32 No 6, Yes None TRIPLE 24 No 427 <20 Failed TRIPLE 24 No 447,557 5,621 Yes V10I, W71T, D76W DUAL-GESIDA 8014-RIS EST-45 study: 48 weeks results 29

28 ANRS 167 LAMIDOL DTG + 3TC as Maintenance Therapy Joly V, et al. CROI Seattle, WA. Poster #458 Inclusion Criteria Current: 2 NRTIs + either NNRTI, PI, or INSTI Maximum of 2 previous ART modifications (simplification or one tolerability switch) Suppressed <50 c/ml for 2 years with no blips in previous 6 months * Wild type virus CD4 nadir >200 cells/mm 3 INDUCTION DTG + 2 NRTIs (n=110) MAINTENANCE DTG + 3TC (n=104) Baseline Week 8 Week 48 & 56 Outcomes INDUCTION: 95% (104/110) eligible for dual therapy MAINTENANCE: 97% (101/104) remained suppressed 1 virologic failure: W4 with VL 84 c/ml 1 therapeutic failure: W40 with blip VL 59 c/ml 1 lost to follow-up: W32 Switching to DTG+3TC maintained virologic suppression in patients without history of virologic failure >18 years Normal labs & HBsAg negative * Subjects were on current ART for a median of 4 years (range: ) 6 subjects were ineligible for Phase 2: 3 with detectable VL and 3 with AEs (1 serious AE of suicide ideation)

29 3TC+PI/r dual therapies as maintenance strategies: resistance at failure 4 randomized controlled studies: 2 ATV/r+3TC (ATLAS, SALT), 96W 1 LPV/r+3TC (OLE) 1 DRV/r+3TC (DUET) NO EMERGING RESISTANCE MUTATIONS AT FAILURE (1 case of M184V in the 3-drug arm of SALT) In observational studies: 1 case of resistance to ATV (V32I-M46L- I50L-V82A) (no M184V) Role of previous M184V in 3TC + PI/r or DTG? 31

30 Patients baseline characteristics in DT group (n=454) M184V- (n=365) M184V+ (n=89) p Age, years* 47 (40;54) 52 (48;57) <0.001 Male gender 265 (73%) 52 (58%) Caucasian 322 (88%) 86 (97%) Risk factor sexual IDU other 28% 232 (64%) 44(12%) 89 (24%) 58 (65%) 21 (24%) 10 (11%) HCV co-infection 68 (19%) 24 (27%) HBsAg+ 14 (4%) 2 (2%) TC+DRV/r Previous AIDS events 41 (11%) 16 (18%) Years from HIV diagnosis* 8 (4;14) 19 (16;23) 3TC+DTG <0.001 Years from first cart initiation* 37% 6 (3;11) 17 (13;19) 3TC+RAL <0.001 CD4 nadir, cells/µl* 224 (81;310) 131 (52;199) <0.001 CD4, cells/µl* 627 (462;786) 616 (409;899) Previous major PI resistance mutations 12 (3%) 29 (33%) <0.001 Type of DT: 3TC+PI/r 254 (70%) 67 (75%) TC+INI 111 (30%) 22 (25%) Calendar year of BL 2014 (2013;2015) 2014 (2012; 2015) Gagliardini R 15th European MHH, 2017 Values are expressed as n (%) except for * median (IQR) Dual therapies 1% 10% 24% 3TC+LPV/r 3TC+ATV/r 0.002

31 Virological outcomes on dual therapies Overall incidence of VF: 2.35 per 100 PYFU 13 over 572 PYFU in M184V- pts (2.27 per 100 PYFU) 4 over 153 PYFU in M184V+ pts (2.63 per 100 PYFU) 3 DRV/r+3TC, 1 ATV/r+3TC Median follow-up: 1.2 years (IQR ) Estimated probability of remaining free from VF with dual therapy at 3 years M184V- 92.5% (95% CI 87.2; 97.8) M184V+ 92.5% (95% CI 85.0; 99.9) p=0.824 Virological blips occurred in 29/352 (8%) M184V- pts and 15/84 (18%) M184V+ (p=0.009). Gagliardini R 15th European MHH, 2017

32 Virological outcomes on dual therapies vs monotherapies Overall dual therapy versus monotherapy Dual therapy M184V+ versus monotherapy Estimated probability of remaining free of VF at 3 years DT 92.5% (95% CI 87.9; 97.0) Mono 81.5% (95% CI 73.1; 89.9) p<0.001 Estimated probability of remaining free of VF at 3 years DT M184V+ 92.5% (95% CI 85.0; 99.9) Mono 81.5% (95% CI 73.1; 89.9) p=0.049 Gagliardini R 15th European MHH, 2017

33 HIV-1 RNA <50 c/ml, % SWORD 1 and 2: Switching to DTG+RPV vs Maintaining CAR Snapshot Outcomes at Week 48 (Pooled) Virologic outcomes DTG + RPV (n=513) CAR (n=511) Adjusted treatment difference (95% CI)* CAR DTG + RPV 0 Virologic success <1 1 Virologic non-response 5 4 No virologic data Percentage-point difference * Adjusted for age and baseline 3 rd agent. Llibre JM, et al. CROI Seattle, WA. Oral #44LB

34 Mean Adjusted Change in BMD From BL (%) SWORD 1 & 2 Substudy: BMD Impact of Switch From TDF-Based ART to DTG + RPV Randomized, open-label, multicenter phase III trials demonstrated that switch to DTG + RPV noninferior to remaining on baseline ART at Wk 48 in virologically suppressed pts [1] Current analysis assessed BMD in pts who continued on TDF-containing triple ART regimen or switched from TDF-containing triple ART to DTG + RPV (N = 102) [2] Change From BL in BMD at Wk P = P = DTG + RPV (n = 46) Continued TDF-based ART (n = 35) BL 48 Wks BL 48 Wks *Primary endpoint. Total Hip* Lumbar Spine 1. Llibre JM, et al. CROI Abstract 44LB. 2. McComsey G, et al. IAS Abstract TUPDB0205LB. Reproduced with permission. Slide credit: clinicaloptions.com

35 Pts (%) LATTE-2: 96-Wk Results for Cabotegravir IM + Rilpivirine IM as Long-Acting Maintenance ART Cabotegravir: INSTI formulated as PO tablet and for long-acting IM injection LATTE-2: phase IIb study in which pts randomized to CAB 400 mg IM + RPV 600 mg Q4W, CAB 600 mg IM + RPV 900 mg Q8W, or CAB 30 mg PO + ABC/3TC 600/300 mg QD after induction/ virologic suppression with oral CAB + ABC/3TC (N = 309) [1,2] Virologic Success* *HIV-1 RNA < 50 copies/ml. References in slidenotes. Wk 96 Virologic Efficacy CAB IM + RPV Q4W (n = 115) CAB IM + RPV Q8W (n = 115) CAB PO + ABC/3TC (n = 56) Treatment Difference vs CAB PO (95% CI) CAB IM Q4W: 3.0% (-8.4% to 14.4%) CAB IM Q8W: 10.0% (-0.6% to 20.5%) Virologic Nonresponse No Virologic Data At 96 wks, ~ 30% of pts receiving IM injection experienced ISR 99% of ISRs mild/moderate Withdrawals between Wks 48 and 96: CAB IM arms, n = 4 (n = 1 for AE, n = 3 withdrew consent); CAB PO arm, n = 3 (all withdrew consent) No additional PDVFs after Wk 48 in any arm ~ 88% of pts receiving CAB IM very satisfied to continue present treatment at Wk 96 vs 43% receiving CAB PO Phase III maintenance trials (ATLAS and FLAIR) moving forward with Q4W dose [3,4] Slide credit: clinicaloptions.com

36 Dual therapies: considerations Most solid evidence of efficacy in maintenance therapy PI/r+3TC (..and M184V does not preclude its activity): no resistance selection DTG+RPV Caveat: PI/r tolerability? Toxicity benefits of dual vs triple: Bone and renal, due to TDF discontinuation Will TAF avoid the need of dual? Reduced costs Not for all dual therapies DTG + 3TC future game changer? Naive, maintenance Beyond efficacy, tolerability and costs will still count Previous M184V? Resistance selection?