X Congreso Nacional de GESIDA Sesión Plenaria GESIDA Nuevas Modalidades de Tratamiento Antirretroviral

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1 X Congreso Nacional de GESIDA Sesión Plenaria Nuevas Modalidades de Tratamiento Antirretroviral Dr. José M. Miró Servicio de Enfermedades Infecciosas Hospital Clínic - IDIBAPS Universidad de Barcelona Barcelona Correo electrónico: jmmiro@ub.edu

2 Potential conflict of interest Dr. José M Miró has received honoraria for speaking or participating in Advisory Boards and/or research grants from the following Pharmaceutical Companies: Abbvie Contrafect Cubist Genentech Gilead Sciences Jansen-Cilag Merck Novartis Pfizer Roche Theravance ViiV Healthcare

3 New Modalities of Antiretroviral Treatment Where we come from: Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages

4 THE EVOLUTION OF HIV THERAPY >30 ARTS 1984 STR 2018 Retrovir 100 mg capsule <50 cop./ml InSTI FDA. Antiretroviral drugs used in the treatment of HIV infection Accessed August 2015 FDA news release November Accessed November 2015

5 Hosp. Clinic-IDIBAPS-Univ. of Barcelona, Barcelona, Spain Hospital Clinic of Barcelona HIV cohort ( ) 8,500 patients (historical cohort) 5,300 active patients 5,100 (95%) on ART (>95% VL BDL)

6 Number of new and accumulated HIV-infected patients and patients on ART at the H. Clinic of Barcelona ( ) 5267 patients 98% on ART PrEP!!!

7 Percentage of patients with undetectable HIV RNA viral load (<400 c/ml) on ART at the H. Clinic of Barcelona ( ) 97% 50% 80-90% 0% Lee FJ et al PLoS One 2014;9:e97482; Carr A et al. Glasgow 2018 P#51

8 Annual mortality rates in the cohort of HIV-infected patients of the H. Clinic of Barcelona ( ) 20% <1%

9 The Constant Evolution of Initial ART at the Hospital Clinic of Barcelona, Spain ( ) 12 /r/c InSTI = 60%

10 New Modalities of Antiretroviral Treatment Where we come from: Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages

11 Saag MS et al. JAMA. 2018; 320:

12 Recommended Initial ART Regimens for Treating HIV Infection in 2018 Saag MS et al. JAMA. 2018;320:

13 Alternative ART Regimens for Treating HIV Infection in 2018 Saag MS et al. JAMA. 2018;320:

14 96 wk. Results Presented at the IDWeek and HIV Glasgow Meetings in 2018 B/F/TAF vs. DTG/3TC/ABC B/F/TAF vs. DTG plus TAF/FTC

15 B/F/TAF vs. DTG/3TC/ABC Gallant J, et al. Lancet. 2017;390: & Wohl D et al. IDWeek. October 3-7, 2018

16 B/F/TAF vs. DTG/3TC/ABC Gallant J, et al. Lancet. 2017;390: & Wohl D et al. IDWeek. October 3-7, 2018

17 92% vs. 93% at W48 B/F/TAF vs. DTG/3TC/ABC No R mutations AE D/C = 0/5 Gallant J, et al. Lancet. 2017;390: & Wohl D et al. IDWeek. October 3-7, 2018

18 GS-US Study Design B/F/TAF vs. DTG plus TAF/FTC 1 Endpoint 2º Endpoint Week Treatment-Naïve Adults HIV-1 RNA 500 c/ml egfr CG 30 ml/min 1:1 n=320 n=325 B/F/TAF QD DTG + F/TAF Placebo QD DTG + F/TAF QD B/F/TAF Placebo QD Phase 3, randomized, double-blind, active-controlled study Stratified by HIV-1 RNA, CD4 cell count, geographic region (USA vs non-usa) North America, Europe, Australia, and Latin America Chronic hepatitis B and/or C virus (HBV/HCV) infection allowed Primary endpoint: proportion with HIV-1 RNA <50 copies/ml at Week 48 B/F/TAF 89.4% vs DTG + F/TAF 92.9% with HIV-1 RNA <50 c/ml (p=0.12) 1 Secondary endpoint: proportion with HIV-1 RNA <50 copies/ml at Week 96 Noninferiority margin of 12% based on FDA Snapshot algorithm ClinicalTrials.gov NCT c, copies; egfr CG, estimated glomerular filtration rate by Cockcroft-Gault equation. 1. Sax et al. Lancet 2017; 390: Stellbrink HJ et al. HIV Glasgow. October 28-31,

19 Baseline Characteristics B/F/TAF vs. DTG plus TAF/FTC B/F/TAF n=320 DTG + F/TAF n=325 Median age, y (range) 33 (18 71) 34 (18 77) Male, % Race/ethnicity, % Black or African descent White Hispanic/Latino Median HIV-1 RNA, log 10 copies/ml (Q1, Q3) 4.43 (3.95, 4.90) 4.45 (4.03, 4.84) HIV-1 RNA >100,000 copies/ml, % Median CD4 cell count, cells/µl (Q1, Q3) 440 (289, 591) 441 (297, 597) CD4 count <200 cells/µl, % HBV*/HCV coinfection, % 3/2 2/2 Median egfr CG, ml/min (Q1, Q3) 120 (101, 142) 121 (103, 145) c, copies; egfr CG, estimated glomerular filtration rate by Cockcroft-Gault; IQR, interquartile range. * Positive HBV surface antigen; isolated positive HBV core antigen, with quantifiable HBV DNA (ie, 20 IU/mL) on or prior to 1st dose. Positive HCV antibody and quantifiable HCV RNA (ie, 15 IU/mL) prior to 1st dose of study drug. Sax PE, et al. Lancet. 2017;390: & Stellbrink HJ et al. HIV Glasgow. October 28-31,

20 Proportion of participants, % Virologic Outcome at Week 96 Snapshot analysis 89% vs. 93% at W Virologic Outcome B/F/TAF vs. DTG plus TAF/FTC B/F/TAF (n=320) DTG + F/TAF (n=325) % Treatment Difference (95% CI) Favors DTG + F/TAF Favors B/F/TAF HIV-1 RNA <50 copies/ml At Week 96, B/F/TAF was noninferior to DTG + F/TAF by FDA Snapshot analysis Per protocol analysis: B/F/TAF 100% vs DTG + F/TAF 98% Mean CD4 increase from baseline at Week 96: B/F/TAF +237 cells/µl vs DTG + F/TAF +281 cells/µl (p=0.008) Mean CD4 % change B/F/TAF 11% vs DTG + F/TAF 11% (p=0.37) Mean absolute CD4 B/F/TAF 693 vs DTG + F/TAF 733 (p=0.13) 4 3 HIV-1 RNA 50 copies/ml P-value was from analysis of variance (ANOVA) model adjusted by the baseline HIV-1 RNA and region stratum No Virologic Data No R mutations AE D/C = 6/5 Sax PE, et al. Lancet. 2017;390: & Stellbrink HJ et al. HIV Glasgow. October 28-31,

21 B/F/TAF vs. DTG/3TC/ABC vs. DTG plus TAF/FTC Pros - Same day T&T w/str - HBV Cons - Acute infection - Advanced Infection - Avoid in TB/HIV - Less long-term data Pros - More long-term data - TB/HIV Cons - HLA-B*5701 testing - Same day T&T w/taf/ftc - HBV w/taf/ftc - Advanced Infection - NRC (DTG) and CVD (ABC) issues - Teratogenicity (e.g. NTD)

22 Evolution of ART regimens over time Future 12 /r/c 2 1

23 New Modalities of Antiretroviral Treatment Where we come from: Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages

24 What are the reasons to start/switch to 2DC To avoid potential NRTI-related toxicity - Bone - Kidney - Cardiovascular - Other Less exposure to ART drugs throughout life Economic cost Naïve or virologically suppressed patients No antiretroviral-resistance mutations Never do it in HBV/HIV coinfected patients

25 r/pi-based 2DC 2D vs. TT RCT Naïve - GARDEL (LPV/r + 3TC) - KALEA (LPV/r + TDF) - NEAT001/ANRS143 (DRV/r + RAL)* - ANDES (DRV/r + 3TC) Switching - OLE (LPV/r + 3TC) - ATLAS-M (ATV/r + 3TC) - SALT (ATV/r + 3TC) - DUAL-GESIDA (DRV/r + 3TC) *Not recommended if plasma HIV RNA VL > copies/ml and CD4 < 200/mm3

26 bpi-based 2DC: Trial Designs Study Follow Up Dual Triple Treatment History Week GARDEL (n=306) 96 LPV/r + 3TC LPV/r + 2 NRTI Naïve KALEAD (n=152) 24 LPV/r + TDF LPV/r + 2 NRTI Naïve ANDES (n=145) 48 DRV/r + 3TC DRV/r + 3TC/TDF Naïve OLE (n=250) 48 LPV/r + 3TC LPV/r + 2 NRTI Switch ATLAS-M (n=266) 96 ATV/r + 3TC ATV/r + 2 NRTI Switch SALT (n=267) 96 ATV/r + 3TC ATV/r + 2 NRTI Switch DUAL-GESIDA (n=249) 48 DRV/r + 3TC DRV/r + 2 NRTI Switch Total (n=1635) Liev Z et al. HIV Glasgow. October 28-31, 2018

27 bpi-based 2DC: HIV-RNA <50 copies/ml Study Follow Up Week Dual Triple RD, 95% Confidence Interval GARDEL (n=306) % 84.4% +6% (-2%, +13%) KALEAD (n=152) % 70.0% -1% (-15%, +14%) ANDES (n=145) % 94.2% -1% (-9%, +7%) OLE (n=250) % 86.6% +1% (-7%, +9%) ATLAS-M (n=266) % 65.4% +12% (1 %, +23%) SALT (n=267) % 73.4% +1% (-10%, +11%) DUAL-GESIDA (n=249) % 92.7% -4% (-11%, +3%) Total (n=1635) p= % 80.6% +2% (-2%, +6%) Liev Z et al. HIV Glasgow. October 28-31, 2018

28 bpi-based 2DC: Virological failure (PDVF) Study Follow Up Week Dual Triple RD, 95% Confidence Interval GARDEL (n=306) % 6.4% +1% (5%, +7%) KALEAD (n=152) % 8.8% -7% (-4%, +17%) ANDES (n=145) % 1.4% -1% (-5%, +2%) OLE (n=250) % 2.4% 0% (-4%, +4%) ATLAS-M (n=266) % 6.8% -5% (-10%, - 1%) SALT (n=267) % 3.7% +3% (-2%, +8%) DUAL-GESIDA (n=249) % 1.6% +2% (-2%, +8%) Total (n=1635) p= % 4.5% 0% (-2%,+2%) Liev Z et al. HIV Glasgow. October 28-31, 2018

29 Treatment Emergent Resistance Mutations Study Follow Up Week Dual Triple RD, 95% Confidence Interval GARDEL (n=306) % 2.1% -1% (-5%, +2%) KALEAD (n=152) % 1.3% -1% (-5%, +2%) OLE (n=250) % 0.0% +1% (-1%, +1%) ATLAS-M (n=266) % 0.0% 0% (-1%, +1%) SALT (n=267) % 0.7% -1% (-3%, +1%) DUAL-GESIDA (n=249) % 0.0% -1% (-1%, +1%) Total (n=1490) p= % 0.7% 0% (-1%, +1%) Only few NRTI mutations in 2D and TT arms (M184V). No major PI mutations. Liev Z et al. HIV Glasgow. October 28-31, 2018

30 Discontinuations due to Adverse Events Study Follow Up Week Dual Triple RD, 95% Confidence Interval KALEAD (n=152) % 7.5% +4% (-6%, +13%) TDF (n=152) p= % 7.5% +4% (-6%, 13%) GARDEL (n=306) % 2.8% -2% (-5%, +1%) OLE (n=250) % 3.1% -2% (-6%, +1%) ATLAS-M (n=266) % 2.3% -1% (-4%, +3%) SALT (n=281) % 7.1% -2% (-8%, +3%) DUAL-GESIDA (n=249) % 1.6% -1% (-4%, +2%) 3TC (n=1352) p= % 3.5% -2% (-3%, 0%)

31 Percentage of patients who achieved endpoint ( %) bpi-based 2DC: Summary Findings Dual Triple % 80.6% <50cp/ml PDVF Resistance D/AE HIV-RNA <50 copies/ml Dual Triple 5.0% 4.5% Protocol Defined Virological Failure Dual Triple 0.7% 0.7% Resistance Mutations Dual Triple 2.7% 3.9% Discontinuations due to adverse events

32 r/pi-based 2DC 2D vs. TT RCT DTG-based 2DC Naïve - GARDEL (LPV/r + 3TC) - KALEA (LPV/r + TDF) - NEAT001/ANRS143 (DRV/r + RAL) - ANDES (DRV/r + 3TC) Switching - OLE (LPV/r + 3TC) - ATLAS-M (ATV/r + 3TC) - SALT (ATV/r + 3TC) - DUAL-GESIDA (DRV/r + 3TC) Naïve (+ 3TC) - PADDLE (single arm) - ACTG A5353 (single arm) - GEMINI 1+2 (DTG + 3TC) Switching - SWORD 1+2 (DTG + RPV) - ASPIRE (DTG + 3TC) - ANRS 167 LAMIDOL (single arm DTG + 3TC)

33 GEMINI-1 and -2 Phase III Study Design Identically designed, randomized, double-blind, parallel-group, multicenter, noninferiority studies Screening (28 d) 1:1 Double-blind phase Open-label phase Continuation phase ART-naive adults VL ,000 c/ml DTG + 3TC (N=716) DTG + TDF/FTC (N=717) DTG + 3TC Day 1 Week 24 Week 48 Week 96 Week 144 Eligibility criteria 10 days of prior ART No evidence of pre-existing viral resistance based on presence of any major resistanceassociated mutation No HBV infection or need for HCV therapy Primary endpoint at Week 48: participants with HIV-1 RNA <50 c/ml (ITT-E snapshot) a Countries Argentina Australia Belgium Canada France Germany Italy Republic of Korea Mexico Netherlands Peru Poland Portugal Romania Russian Federation South Africa Spain Switzerland Taiwan United Kingdom United States Baseline stratification factors: plasma HIV-1 RNA ( 100,000 c/ml vs >100,000 c/ml) CD4+ cell count ( 200 cells/mm 3 vs >200 cells/mm 3 ). a 10% noninferiority margin for individual studies. Cahn P et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB. 22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands

34 Demographic and Baseline Characteristics for the Pooled GEMINI-1 and -2 Population Characteristic DTG + 3TC (N=716) DTG + TDF/FTC (N=717) Age, median (range), y 50 y, n (%) 32.0 (18-72) 65 (9) 33.0 (18-70) 80 (11) Female, n (%) 113 (16) 98 (14) Race, n (%) African American/African heritage Asian White Other Ethnicity, n (%) Hispanic or Latino Not Hispanic or Latino HIV-1 RNA, median (range), log 10 c/ml 100,000 >100,000 a up to 500, (14) 71 (10) 480 (67) 66 (9) 215 (30) 501 (70) 4.43 ( ) 576 (80) 140 (20) 76 (11) 72 (10) 497 (69) 72 (10) 232 (32) 485 (68) 4.46 ( ) 564 (79) 153 (21) CD4+ cell count, median (range), cells/mm 3 > a 2% of participants in each arm had baseline HIV-1 RNA >500,000 c/ml ( ) 653 (91) 63 (9) ( ) 662 (92) 55 (8) Cahn P et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB. 22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands

35 Pooled Snapshot Outcomes at Week 48: ITT-E and Per Protocol Populations Virologic outcome Adjusted treatment difference (95% CI) a ITT-E DTG + 3TC (N=716) DTG + TDF/FTC (N=717) PP b DTG + 3TC (N=694) DTG + TDF/FTC (N=693) DTG + TDF/FTC DTG + 3TC ITT-E PP Percentage-point difference DTG + 3TC is non-inferior to DTG + TDF/FTC with respect to proportion <50 c/ml at Week 48 (snapshot, ITT-E population) in both studies a Based on Cochran-Mantel-Haenszel stratified analysis adjusting for the following baseline stratification factors: plasma HIV-1 RNA ( 100,000 c/ml vs >100,000 c/ml), CD4+ cell count ( 200 cells/mm 3 vs >200 cells/mm 3 ), and study (GEMINI-1 vs GEMINI-2). b PP, per protocol: population consisted of participants in the ITT-E population except for significant protocol violators, which could potentially affect efficacy outcomes as determined by the medical monitor prior to database lock. Cahn P et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB. 22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands

36 Pooled Outcomes at Week 48 Stratified by Baseline HIV-1 RNA and CD4+ Cell Count: Snapshot and TRDF Analysis Snapshot Analysis TRDF Analysis ,000 >100,000 > Baseline HIV-1 RNA, c/ml Baseline CD4+ cell count, cell/mm 3 100,000 >100,000 > Baseline HIV-1 RNA, c/ml Baseline CD4+ cell count, cell/mm 3 DTG + 3TC DTG + TDF/FTC 2% of participants in each arm had baseline HIV-1 RNA >500,000 c/ml. Treatment related discontinuation = failure (TRDF) population accounts for confirmed virologic withdrawal (CVW), withdrawal due to lack of efficacy, withdrawal due to treatment-related AE, and participants who met protocol-defined stopping criteria. DTG + 3TC CD4 <200 Snapshot non-response (n=13): 1 CVW, 3 with VL >50 in window (2 of 3 re-suppressed), 2 discontinued due to AE (TB, Chagas disease), 2 protocol violations, 2 lost to follow-up, 1 withdrew consent, 1 withdrew to start HCV treatment, 1 change in ART (incarcerated). DTG + TDF/FTC < 200 Snapshot non-response (n=4):1 investigator discretion, 1 withdrew consent, 1 lost to follow-up, 1 VL >50 (re-suppressed). Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB. 22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands

37 Confirmed Virologic Withdrawals Through Week 48: ITT-E Population Low rates of virologic withdrawals were observed at Week 48 Variable, n (%) DTG + 3TC (N=356) GEMINI 1 GEMINI 2 Pooled DTG + TDF/FTC (N=358) DTG + 3TC (N=360) DTG + TDF/FTC (N=359) DTG + 3TC (N=716) DTG + TDF/FTC (N=717) CVW 4 (1) 2 (<1) 2 (<1) 2 (<1) 6 (<1) 4 (<1) Treatment-emergent resistance No treatment-emergent INSTI mutations or NRTI mutations were observed among participants who met CVW (confirmed virologic failure) criteria Confirmed virologic withdrawal criteria is defined as a second and consecutive HIV-1 RNA value meeting virologic non-response or rebound. Virologic non-response is defined as either a decrease in plasma HIV-1 RNA of less than 1 log 10 c/ml by Week 12 with subsequent confirmation unless plasma HIV-1 RNA is <200 c/ml, or confirmed plasma HIV-1 RNA levels 200 c/ml on or after Week 24. Virologic rebound is defined as confirmed rebound in plasma HIV-1 RNA levels to 200 c/ml after prior confirmed suppression to <200 c/ml.. Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB. 22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands

38 SWORD-1 and -2: Phase III Study Design Identically designed, randomised, multicentre, open-label, parallel-group, non-inferiority studies Screening VL <50 c/ml on INI, NNRTI, or PI + 2 NRTIs 1:1 Early-switch phase Late-switch phase Continuation phase DTG + RPV (N=513) CAR (N=511) DTG + RPV DTG + RPV Day 1 Inclusion criteria On stable CAR 6 months before screening 1st or 2nd 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 Week 52 Primary endpoint at 48 weeks: subjects with VL <50 c/ml (ITT-E snapshot) * Week 148 Countries: Argentina Australia Belgium Canada France Germany Italy Netherlands Russia Spain Taiwan United Kingdom United States *8% non-inferiority margin for pooled data. -10% non-inferiority margin for individual studies HBV, hepatitis B virus; ITT(-E), intent to treat (- exposed); NRTI, nucleoside reverse transcriptase inhibitor Llibre JM, et al. CROI Oral Presentation 44LB

39 SWORD-1 and -2: Demographics and Baseline Characteristics Age, mean (SD) 50 years DTG + RPV (n=513) n (%) 43 (11) 147 (29) CAR (n=511) n (%) 43 (10) 142 (28) Female 120 (23) 108 (21) Race, non-white 92 (18) 111 (22) CD4+ cell count, cells/mm 3 (median) 500 >500 Baseline third-agent class PI NNRTI INI (32) 348 (68) 133 (26) 275 (54) 105 (20) (29) 362 (71) 136 (27) 278 (54) 97 (19) Baseline TDF use 374 (73) 359 (70) Median duration of ART prior to Day 1, months Data pooled across SWORD-1 and -2 Llibre JM, et al. CROI Oral Presentation 44LB

40 SWORD-1 and -2: Snapshot Outcomes at Week 48 Virologic outcomes Adjusted treatment difference (95% CI) * SWORD-1 CAR DTG + RPV SWORD-2 SWORD SWORD <1 <1 < Percentage-point difference DTG + RPV is non-inferior to CAR with respect to snapshot in the ITT-E population (<50 c/ml) at Week 48 in both studies * Adjusted for age and baseline third agent Llibre JM, et al. CROI Oral Presentation 44LB

41 SWORD-1 and -2: Confirmed Virologic Withdrawals DTG + RPV n=513 n (%) Early-switch phase CAR n=511 n (%) CVW * 2 (<1) 2 (<1) One subject on DTG + RPV meeting virologic withdrawal criteria had an NNRTI resistance-associated mutation (K101K/E) identified No INI resistance-associated mutations were identified Data pooled across SWORD-1 and -2 *CVW defined as current retest HIV-1 RNA 200 c/ml, prior 50 c/ml CVW, confirmed virologic withdrawal Llibre JM, et al. CROI Oral Presentation 44LB

42 Evolution of ART regimens over time 2D or not 2D that is the question Hamlet, Act III, Scene I. Sir William Shakespeare,

43 Uptake and effectiveness of 2D compared to TT ART regimens in Europe 2D ART regimens ART response at 48 wk. Switching ART in >80% of cases Pelchen-Matthews A et al. EuroSida. IAS. Amsterdam, 2018 Poster No. THPEB052

44 Pros Pros - Potential Excellent efficacy 2DC & RCTs safety data in naïve patients - More long-term data - No bpi mutations - bpi can be used in CKD Cons - DDIs - No STRs - b/pi-side effects 2D vs. TT RCT r/pi-based 2DC DTG+3TC vs. bdrv+3tc DTG-based 2DC - Excellent efficacy & safety data - STRs (DTG+RPV, DTG+3TC soon) - No DDIs - No DTG mutations - DTG + RPV can be used in CKD BIC+3TC vs. DTG+3TC or bdrv+3tc DTG+3TC in Acute-Recent/Advanced Patients Cons - Limited data in acute/recent infection - Limited data in advanced patients - DTG-side effects - RPV must be taken with food, avoid PPIs and separated from antiacids.

45 New Modalities of Antiretroviral Treatment Where we come from: Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages

46 What are the reasons to use long-acting (LA) antiretrovirals for treating HIV-infection Adherence to oral antiretrovirals can be variable Special populations - Drug and alcohol abuse - Psychiatric illness Antiretroviral stigma Patients preference Monroe M et al. Bioengineering & Translational Medicine 2018;3:

47 Main Characteristics of LA ARV drugs Requirements Infrequent dosing (~ 2-3 months) Practical injection volume ( 4mL) Minimal PK tail High genetic barrier to resistance Minimal injection associated adverse events Stable formulation ideally without cold chain requirements LA ARV drugs LA Rilpivirine LA Cabotegravir MK-8591 (EFdA)* GS-CA1 (Capsid inhibitor)** Broadly Neutralizing Monoclonal antibodies (PRO140; UB-421; VRC01; VRC01- LS; 3BNC117; ) *Nucleoside reverse transcriptase translocation inhibitor inhibits reverse transcriptase by two different mechanisms. Implant Formulations Release Effective Drug Levels for >180 days; ** Capsid inhibitor. It is the most potent antiretroviral agent.

48 Cabotegravir (CAB) LA Single Injection Provides Detectable Drug in Plasma for 48 Weeks Mean Concentration-Time Profile (n=6/cohort) 100mg IM 200mg IM 400mg IM 800mg IM (split) 100mg SC 200mg SC 400mg SC (split) Plasma CAB ( g/ml) CAB LA apparent half-life ~40days versus CAB oral ~40hr half-life 4*PA-IC90 PA-IC90 (0.67 ug/ml) CAB 5mg/day p.o. C tau = 0.6 ug/ml Very very long PK tail! Time (weeks) 48 Spreen W et al. JAIDS 2014;67:

49 Proportion, % (95% CI) Parenteral Cabotegravir + Rilpivirine as Long- Acting Maintenance Therapy: LATTE-1 RCT CAB is an HIV-1 integrase inhibitor Oral 30 mg tablet (t½, ~40 hours) LA nanosuspension 200 mg/ml (t½, ~20-40 days) RPV is an HIV-1 NNRTI Oral 25 mg tablet (t½, ~50 hours) LA nanosuspension 300 mg/ml (t½, ~30-90 days) Oral 2-drug CAB + RPV proof of efficacy through Week 96 in LATTE BL CAB 10 mg (n=60) CAB 60 mg (n=61) CAB 30 mg (n=60) EFV 600 mg (n=62) BL, baseline; CAB, cabotegravir; CI, confidence interval; EFV, efavirenz; LA, long-acting; NNRTI, non-nucleoside reverse transcriptase inhibitor; RPV, rilpivirine; t 1/2, half-life. Margolis et al. Lancet ID. 2015; 15: rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

50 LATTE-2 Study Design (Phase 2) Induction period Maintenance period a CAB 30 CAB mg 30 + mg ABC/3TC + PO QD ABC/3TC for for 20 weeks 20 weeks (N=309) Inclusion criteria CAB loading dose at Day 1 Exclusion criteria CAB loading doses at Day 1 and Week 4 >18 years old Naive to antiretroviral therapy CD4+ >200 cells/mm 3 CAB 400 mg IM + RPV 600 mg IM Q4W (n=115) Positive for hepatitis B ALT 5 ULN Creatinine clearance <50 ml/min CAB 600 mg IM + RPV 900 mg IM Q8W (n=115) Add RPV PO QD 4 weeks Qualification for maintenance CAB 30 mg + ABC/3TC PO QD (n=56) Day 1 Randomization 2:2:1 286/309 (92,5%) HIV-1 RNA <50 c/ml between Week -4 and Day 1 Week 32 Primary analysis Dosing regimen selection Week 48 Analysis Dosing regimen confirmation Week 96 b ABC/3TC, abacavir/lamivudine; ALT, alanine aminotransferase; IM, intramuscular; PO, orally; QD, once daily; Q4W, every 4 weeks; Q8W, every 8 weeks; ULN, upper limit of normal. a Subjects who withdrew after at least 1 IM dose entered the long-term follow-up period. b Subjects can elect to enter Q4W and Q8W LA Extension Phase beyond Week 96. Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB. 21st International AIDS Conference; July 18-22, 2016; Durban, South Africa

51 LATTE 2. HIV-1 RNA <50 c/ml at 48 wk. ITT-ME (Snapshot) Virologic outcomes ITT-e (286 out of 309) Treatment differences (95% CI) Oral IM Q8W IM (CAB RPV 900 mg) Q4W IM (CAB RPV 600 mg) Margolis et al. Lancet ID 2015; 15: st International AIDS Conference; July 18-22, 2016; Durban, South Africa Abstract THAB0206LB.

52 LATTE 2. HIV-1 RNA <50 c/ml at 96 wk. ITT-ME (Snapshot) 90% Q8W vs. 83% Q4W at W160* Virologic outcomes Treatment differences (95% CI) Oral IM Q8W IM 0.6% 20.5% Q4W IM 8.4% 14.4% ITT-ME, intent-to-treat maintenance exposed; LA, long acting; Q4W, every 4 weeks; Q8W, every 8 weeks. Eron et al. IAS 2017; Paris, France. MOAX0205LB; * Margolis DA et al. HIV Glasgow, UK, October 28-31, th IAS Conference on HIV Science; July 23-26, 2017; Paris, France

53 Mean plasma CAB ± SD, μg/ml Mean plasma RPV ± SD, ng/ml LATTE 2. PK of CAB + RPV Q4W and Q8W Q4W Q8W PA-IC90 10 mg PO Cτ 30 mg PO Cτ Q4W Q8W PA-IC90 25 mg PO Cτ Week st International AIDS Conference; July 18-22, 2016; Durban, South Africa 10 Week Phase 3 FLAIR (NCT ), n=570. CAB-LA + RPV-LA Q4 wk. vs. DTG/ABC/3TC in Naives. Fully recruited. Both Phase Q4W 3 and ATLAS Q8W (NCT ), steady state exposures n=570. Switch approximate from any triple once-daily ART (2NRTIs oral dosing + 3rd drug) to CAB LA + RPV LA Q4 wk. Fully recruited. Phase 3 ATLAS 2M, n=1020. Switch from any triple ART to CAB LA +RPV LA Q4 or Q8 wk. Fully recruited. Cτ, trough concentration; PA-IC90, protein binding adjusted 90% inhibitory concentration; SD, standard deviation. Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.

54 Evolution of ART regimens over time LA or not LA that is the question Hamlet, Act III, Scene I. Sir William Shakespeare,

55 Long-Acting (LA) ART Pros - Innovative approach - Excellent efficacy data - Safety (except ISR) - Useful for non-adherent target populations - Also useful for PrEP Cons - No data in VS patients with CD4<200/mm3 - Lead-in oral phase duration not well defined - Best schedule not defined yet - Drug toxicity management - Resistance concern - Limited PK data in sanctuaries - Stopping rules not defined (long PK tail) - Logistics outside RCT

56 New Modalities of Antiretroviral Treatment Where we come from: Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages

57 Naïve - MONARK (LPV/r)* - IMANI I, II (LPV/r)* Monotherapy PI/r-Monotherapy Switching - OK / OK04 (LPV/r) - KALMO / IMANI III (LPV/r) - ACTG5201 (ATV/r)* - ATARIMO / OREY (ATV/r)* - MONET / MONOI / MONARCH (DRV/r) *Hight rates of treatment failures

58 PI/r monotherapy Not recommended in naïve patients LPV/r and DRV/r demonstrated the non-inferiority in switching trials Strict adherence is necessary VF not associated with PI R mutations Most patients resupressed with TT EACS Guidelines considered this option for selected patients

59 SEMINARIO VIH: ACTUALIZACIÓN EN TRATAMIENTO ANTIRRETROVIRAL TRIPLE Y DUAL MOBIDIP/ANRS286 RCT in sub-saharan Africa Randomization 1:1 - HIV-1 VL <200 c/ml 6 mo. PI/r* monotherapy (n=133) - CD4> 100 cels / mm3 - Adherence 90% last control - No ART changes in last 3 mo. 2 NRTI + 1 boosted PI PI/r* + 3TC (n=132) Basal Week 24 Week 96 PI/r Mono PI/r + 3TC Total The patients came from a prospective cohort generated after the 2LADY study Ciaffi L, et al. Lancet HIV 2017;4:e384-e392

60 SEMINARIO VIH: ACTUALIZACIÓN EN TRATAMIENTO ANTIRRETROVIRAL TRIPLE Y DUAL MOBIDIP/ANRS286 RCT in sub-saharan Africa Treatment Failure (ITT análisis) 2% The monotherapy arm was stopped by recommendation of the DSMB 21% Efficacy of the PI/r + 3TC arm at W96 was 92% 7/8 VF were genotyped: without R to PIs or NRTI Ciaffi L, et al. Lancet HIV 2017;4:e384-e392

61 PI/r-Monotherapy Naïve - MONARK (LPV/r) - IMANI I, II (LPV/r) Monotherapy Switching - OK / OK04 (LPV/r) - KALMO / IMANI III (LPV/r) - ACTG5201 (ATV/r) - ATARIMO / OREY (ATV/r) - MONET / MONOI / MONARCH (DRV/r) DTG-Monotherapy Naïve - No studies Switching - DOLAM (TT vs. 2D vs. M) - DOMONO (TT vs. M) - Several cohort studies - Recent HIV Infection (TT vs. M)* *Only study without any case of VF. Braun DL et al. IAS Amsterdam, July 2018.

62 Meta-analysis DTG+3TC and DTG monotherapy Proportion of virologic failures DTG- Mono Mono DTG- Dual Dual Study (n) 24 weeks 48 weeks 24 weeks Proportion (95% CI) 48 weeks Proportion (95% CI) Gubavu et al. (21) 0.00% ( ) Katlama et al. (28) 10.7% ( ) Lecompte et al. (8) 0.00% ( ) Oldenbüttel et al. (31) 3.23% ( ) Rojas et al. (31) 3.23% ( ) Rokx et al. (5) 0.00% ( ) 20.0% ( ) Wijting et al. (96) 2.08% ( ) 8.33% ( ) Borghetti et al. (36) 0.00% ( ) 0% 5% 10% 15% 20% 25% Gantner et al. (116) 0.86% ( ) Virological failure Joly et al. (104) 0.96% ( ) 0.96% ( ) Llibre et al. (513) 0.19% ( ) 0.39% ( ) Maggiolo et al. (94) 0.00% ( ) 0.00% ( ) Reynes et al. (27) 0.00% ( ) 0.00% ( ) Riva et al. (61) 0.00% ( ) SUMMARY 0.8% ( ) 1.14% ( ) 0% 5% 10% 15% 20% 25% Virological failure 3.18% ( ) 8.91% ( ) 0.32% ( ) 0.41% ( ) Buzzi et al. EACS 2017; Milan, Italy. Oral PS1/2.

63 Meta-analysis DTG+3TC and DTG monotherapy Resistances Types of therapy Subjects exposed, n Virological failure Amplified, n New resistances DTG-mono Types of resistance E138K + G140A + Q148R E92Q N155H S230R R263K N155H Q148H + G140S DTG-RPV K101K/E DTG-3TC / DTG-ATZ / On DTG monotherapy, 50% of virological failures develop a new resistance to integrase inhibitors Buzzi et al. EACS 2017; Milan, Italy. Oral PS1/2.

64 Evolution of ART regimens over time Future 12 /r/c 1

65 New Modalities of Antiretroviral Treatment Where we come from: Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages

66 Take Home Messages Current IAS ART guidelines recommend for initial therapy an integrase strand transfer inhibitor (InSTI) (bictegravir or dolutegravir) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs). Dual-therapy regimens that include boosted darunavir or dolutegravir plus lamivudine might be considered for initial therapy in selected non-advanced chronic HIV-infected patients. Dual-therapy regimens that include a boosted protease inhibitor (lopinavir/darunavir) plus lamivudine or dolutegravir plus rilpivirine can be considered for switching therapy in selected virologically suppressed chronic HIV-infected patients. Monotherapy with PIs or dolutegravir as a maintenance strategy is not recommended because of higher rates of treatment failure, often with resistant virus in patients taken dolutegravir monotherapy.

67 Acknowledgements J.R. Arribas A. Calmy E. Lazzari A. Pharris J.M. Llibre E. Martinez G. Mora J. Perez-Molina Jansen Gilead ViiV Healthcare

68 In Memoriam Teresa Gallart Gallart ( ) Servei d Inmunologia Hospital Clínic de Barcelona