What is the magic number? Clinical perspective

What is the magic number? Clinical perspective Andrea De Luca Dipartimento Biotecnologie Mediche Università di Siena UOC Malattie Infettive AOU Senese

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

Number of mono PI or dual PI therapies used according to calendar period of treatment 800 700 719 600 500 400 300 329 413 200 100 0 59 2006-2008 2009-2011 20012-2013 2014-2016 Jan 2017 Report

9% Proportion of mono/dual PI therapies according to calendar period of starting 8,4% 8% 7% 6% 5% 4% 5,2% 3,2% 5,6% 4,7% Dual Mono 3% 2% 1,7% 2,1% 1% 0,7% 0% 2006-2008 2009-2011 2012-2013 2014-2016 Jan 2017 Report

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

% HIV-RNA <200 c/ml DOMONO DTG as Maintenance Monotherapy For HIV-1 100 80 60 40 20 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 92% DTG Mono (N=96) p=0.03 98% 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 W12 678 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) DTG monotherapy efficacy was inferior by Week 48 Wijting I, et al. CROI 2017. Seattle, WA. Poster #451LB 6

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) Virologic Failures (%) Monotherapy (N=122) 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% 9/11 0% Monotherapy Bi / Tri-therapy 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) High rate of genotypic resistance selection after DTG monotherapy failure Summary of available studies: InSTI resistance in 15 of 20 Blanco JL, et al. CROI 2017. Seattle, WA. Oral #42 7

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

Dual therapies in naives Study regimen control n Efficacy outcome Benefits/ Harms Gardel LPV/r+3TC LPV/r+2NA 416 Non-inferior Less AE PADDLE DTG+3TC no 20 20/20 <50 cps at 12m ACTG A5353 DTG+3TC no 120 Includes VL>100K GEMINI DTG+3TC DTG+TVD 700 Modern NEAT001 DRV/r+M VC QD DRV/r+RA L DRV/r+TVD 804 Inferior Bone DRV/r+TVD 805 Non-inferior, inferior with CD4<200 or VL>100K Bone, egfr/insti- R selection

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

Study Maintainance dual ART: completed RCT Previous regimen Study regimen ATLAS-M ATV/r+2NA ATV/r+3TC ATV/r+2N A SALT Any triple ATV/r+3TC ATV/r+2N A OLE LPV/r+2NA LPV/r+3TC LPV/r+2N A DUAL DRV/r+2NA DRV/r+3TC DRV/r+2N A control n Main Efficacy outcome 266 Non-inferior (superior) Benefits/Har ms egfr, bone, AE/lipids 273 Non-inferior Less AE/lipids 250 Non-inferior No/lipids 257 Non-inferior PROBE PI/r+2NA DRV/r+RPV continue 60 Non-Inferior Bone, immune activation/lipids Multineka LPV/r+2NA LPV/r+NVP LPV/r+2N A 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

Study Maintainance dual ART: completed RCT Previous regimen Study regimen control n Main Efficacy outcome LATTE CAB+2NA CAB+RPV EFV+2NA 243 Non-inferior Benefits/Har ms SWORD Any triple DTG+RPV continue 1024 Non-inferior Improved bone turnover markers SPARE LPV+TVD DRV/r+RAL LPV+TVD 58 egfr urinary b2m improved Harness Any triple ATV/r+RAL ATV/r+2 NA 109 Inferior KITE 2NA+X LPV/r+RAL continue 60 Non-inferior no/lipids

Dual therapies as maintenance: uncontrolled/observational studies Pilot studies: DTG+3TC (DOLULAM) DTG+3TC pilot, controlled (ANRS LAMIDOL) Observational studies DRV/r + 3TC DRV/r + ETR DRV/r + RAL LPV/r + RAL ATV + RAL DRV/r+DTG RAL + NVP RAL + ETR DTG + 3TC DTG + RPV Mixed

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

Patients free of treatment failure (ITT S=F) Treatment Difference (95% CI) Favors Triple Favors Dual 96 weeks free of TF: Dual therapy 77.4% (95% CI 70.3-84.5) Triple therapy 65.4% (95% CI 57.3-73.5) +12% +1.2% +22.8% -12% 0 +12%

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)

Causes of treatment failure ATV/rit+3TC N=133 ATV/rit+2 NRTIs N=133 Any cause 30 (22.6) 46 (34.6) 0.030 Virological Failure 2 (1.5)* 9 (6.8) 0.060 Adverse events (potentially treatment-related) i 7 (5.3) 11 (8.3) 0.329 Adverse events (not treatment related) ii 3 (2.3) 5 (3.8) 0.722 Withdrawal of consent 6 (4.5) 9 (6.8) 0.425 Loss to follow up 10 (7.5) 7 (5.3) 0.452 Other 2 (1.5) 5 (3.8) 0.447 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).

Virological failures ID Visit HIV-RNA (cp/ml) CD4 (cells/µl) Comments Dual therapy arm 40 BL 1.452 904 VF at BL, before treatment simplification. GRT: no resistance. 164 W12 64 606 Triple therapy arm 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. 85 W24 16.667 435 No subsequent data, lost to follow-up. 247 W24 7.684 895 Treatment change to elvitegravir/cobicistat/ tenofovir/emtricitabine with virological suppression. GRT PR: 58E. 137 W36 2.797 626 VL <50 cp/ml without treatment change. GRT: no resistance. 168 W36 1.854 597 VL <50 cp/ml without treatment change. GRT: no resistance. 23 W48 26.720 305 VL <50 cp/ml without treatment change. GRT: no resistance. 107 W48 99.999 349 Subsequently lost to follow up. GRT PR: no resistance. 174 W60 22.572 341 230 w84 55 1.137 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. 78 w96 109 674 No subsequent data, lost to follow-up.

Proportion with clinical adverse events ATV/rit + 3TC (N=133) ATV/rit + 2NRTI (N=133) Central Nervous System 7 7 Gastrointestinal 15 16 Skin and soft tissues 8 1 Urinary tract 7 15 Respiratory tract 21 14 Infections 34 36 Neoplasm 5 3 Bone 8 14 Other 33 42 Patients with at least one AE 51/133 (38.3%) 52/133 (39.1%) * Values are expressed as n (%). Overall clinical AE: 138 in DT 148 in TT 8 renal colics 2 in DT 6 in TT

Evolution of renal function

Bone outcomes at 96 weeks Changes in BMD at 96W (%) 2.53 Dual arm TT arm n=73 DT arm: 41 1.77 TT arm: 32 0.69 0.57 Lumbar Spine Total Hip Femoral neck p= ns -1.48 p= ns -2.95 p= 0.02 Bone turnover biomarkers (%) Dual arm TT arm p= ns 14.7 31.83 p= ns p= ns PTH Vitamin p= ns D Osteocalcin FAO -15.62-2,64-14.1-23.3-50.91-45.2

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) Stratified by baseline NRTI Wk 48 Primary endpoint Pts with HIV-1 RNA < 50 copies/ml for > 6 mos; on triple therapy* 2 mos; HBsAg negative (N = 257) 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. Pulido F, et al. HIV Glasgow 2016. Abstract O331.

Sensitivity analysis Proportion ofpatients with HIV viral load <50 copies/ml (%) Difference (%) IC 95% 12 0 3.4-3.8 5.7-2.2 3.9-3.4 2.4-1.7-5.8-12 -11-10.2-10.7 DUAL TRIPLE 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 97% 98% 93% 93% 89% 87% 89% 89% 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 23

Continuous viral load suppression HIV- viral load less than 50 copies/ml in all the visits (%) Blips 100% 100% 82.5% 82.9% 90% 80% 80% 70% 60% 60% 40% DUAL TRIPLE 50% 40% 30% 20% 20% 10% 0% 0% DUAL TRIPLE 13.2% 8.9% 4.5% 2.6% 0.9% 0.0% Single Double Triple p =0.94 p=0.31 p=0.31 p=0.46 Including all patients who completed 48 weeks of treatment and had viral loads measurements in all visits. Only patients who had HIV-RNA < 50 copies at week 48. Blip defined as a transitory viral load 50 copies/ml DUAL-GESIDA 8014-RIS EST-45 study: 48 weeks results 24

Resistance testing (attempted in all rebounds with viral loads > 400 HIV-RNA copies/ml) GROUP DUAL Week Baselin e HIV-RNA 50 c/ml week 48 (SNAPSHOT) 1 st viral load 2 nd viral load Genotype Mutations Yes 80 800 Yes None DUAL 24 Yes 988 259 Failed DUAL 32 No 6,805 165 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 25

ANRS 167 LAMIDOL DTG + 3TC as Maintenance Therapy 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 >18 years Normal labs & HBsAg negative 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 * Subjects were on current ART for a median of 4 years (range: 0.5-11.3) 6 subjects were ineligible for Phase 2: 3 with detectable VL and 3 with AEs (1 serious AE of suicide ideation) Joly V, et al. CROI 2017. Seattle, WA. Poster #458 26

3TC+PI/r dual therapies as simplification 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 see Gagliardini R at this meeting 3TC + ATV/r vs DRV/r in clinical practice: see Di Carlo D #51 at this meeting 27

SWORD 1 and 2: Switching to DTG+RPV vs Maintaining CAR Study Design and Baseline Characteristics * Identically designed, randomised, multicenter, open-label, parallel-group, non-inferiority studies Screening Early Switch Phase VL <50 c/ml on INI, NNRTI or PI + 2 NRTIs Inclusion Criteria On stable CAR 6 months before screening 1 st or 2 nd ART with no change in prior regimen due to VF Confirmed HIV-1 RNA <50 c/ml during the 12 months before screening HBV negative 1:1 DTG + RPV (N=513) CAR (N=511) Day 1 Week 52 Age, mean (SD) 50 years DTG + RPV (n=513) 43 (11.1) 29% CAR (n=511) 43 (10.2) 28% Female 23% 21% Race, non-white 18% 22% CD4+ cell count, cells/mm 3 (median) 500; >500 611 32%; 68% 638 29%; 71% Baseline 3rd-agent class : PI; NNRTI; INI 26%; 54%; 20% 27%; 54%; 19% Baseline TDF use 73% 70% Duration of ART prior to Day 1, median, months 51 53 * Data pooled across SWORD-1 and SWORD-2. DTG, dolutegrevir; RPV, rilpivirine; CAR, combination antiretroviral therapy Llibre JM, et al. CROI 2017. Seattle, WA. Oral #44LB 28

HIV-1 RNA <50 c/ml, % SWORD 1 and 2: Switching to DTG+RPV vs Maintaining CAR Snapshot Outcomes at Week 48 (Pooled) 100 80 95 95 Virologic outcomes DTG + RPV (n=513) CAR (n=511) Adjusted treatment difference (95% CI)* CAR DTG + RPV 60 40 20-0.2-3.0 2.5 0 Virologic success <1 1 Virologic non-response 5 4 No virologic data -8-6 -4-2 0 2 4 6 8 Percentage-point difference * Adjusted for age and baseline 3 rd agent. Llibre JM, et al. CROI 2017. Seattle, WA. Oral #44LB 29

SWORD 1 and 2: Switching to DTG+RPV vs Maintaining CAR Snapshot Outcomes at Week 48 (Pooled) Early Switch Phase * DTG + RPV n=513 n (%) CAR n=511 n (%) Virologic success 486 (95) 485 (95) Virologic non-response 3 (<1) 6 (1) Data in window not <50 c/ml 0 2 (<1) Discontinued for lack of efficacy 2 (<1) 2 (<1) Discontinued while VL not <50 c/ml Change in ART 1 (<1) 0 1 (<1) 1 (<1) No virologic data 24 (5) 20 (4) Discontinued due to AE or death 1 17 (3) 3 (<1) Discontinued for other reasons 7 (1) 16 (3) Missing data during window but on study 0 1 (<1) * Two deaths in the study, both unrelated to study drug. DTG+RPV Kaposi s Sarcoma (N=1), CAR Lung cancer (N=1) Llibre JM, et al. CROI 2017. Seattle, WA. Oral #44LB 30

Mean (µg/l) Switch From Suppressive ART to DTG + RPV: Safety Outcomes DTG + RPV Baseline ART 100 Baseline Baseline Wk 48 Wk 48 80 P <.001 60 40 20 0 53.0 55.354.7 P <.001 45.6 P <.001 23.8 24.0 15.9 16.2 17.1 19.0 23.1 12.9 Bone-specific alkaline phosphatase Osteocalcin Procollagen 1 N-terminal propeptide Bone Turnover Marker AE rates generally similar between treatment arms through Wk 52 Numerically higher rate of drugrelated grade 1/2 AEs with switch: 17% vs 2% Numerically higher rate of withdrawal for AEs with switch: 4% vs < 1% No notable change in serum lipid values from baseline to Wk 48 in either treatment arm Llibre JM, et al. CROI 2017. Abstract 44LB.

Dual therapies: considerations Most solid evidence of efficacy in maintenance therapy PI/r+3TC 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, maintainance Beyond efficacy, tolerability and costs will still count