New Antiretroviral Data BHIVA Bournemouth 2019

Dr. Mindy Clarke

Consultant in HIV & Sexual health Brighton & Sussex University Hospital NHS Trust Honorary Senior Clinical Lecturer Brighton & Sussex Medical School COMPETING INTERESTS OF FINANCIAL VALUE > £1,000: in last 12 months

• Amanda Clarke: has acted in a consultancy capacity for Gilead Sciences and ViiV Healthcare. She has received personal grants for attending conferences from Gilead Sciences. What we’ll cover • Naive– triple & dual • Switch – triple , dual, injectables • Failure • Pipeline • Guideline changes Meet Bob, Sam, Izzy & Ray Bob – been declining Rx, wants new ART, no side effects

Sam – on treatment for years, lots of comorbidities wants to know about switching options

Izzy –fed up of pills, wants to know about injectables

Ray – multidrug resistance, detectable viral load, CD4 declining Meet Bob, Sam, Izzy & Ray Bob – been declining Rx, wants new ART, no side effects

Sam – on treatment for years, lots of comorbidities wants to know about switching options

Izzy –fed up of pills, wants to know about injectables

Ray – multidrug resistance, detectable viral load, CD4 declining Doravirine: treatment naïve – week 96 data once/day, no food requirements Drive Ahead n=728 Drive Forward n=768 • Double blind, RCT, phase III • Double blind RCT, phase III • Doravirine/3TC/TDFvs • Doravirine vs DRV/r + EFV/FTC/TDF 2NRTIs • No resistance, VL>1,000 • No resistance, VL>1,000 copies/mL copies/mL • Week 48 primary endpoint: • Week 48 primary endpoint: 84% v 81% 84% v 80%

1. Orkin. IDWeek 2018. Abstr LB1. 2. Orkin. Clin Infect Dis. 2018;[Epub]. Molina JM, et al. AIDS 2018. Abstract LBPEB017. Doravirine Week 96 data FDA snapshot analyses Drive Ahead (vs EFV/3TC/TDF) Drive Forward (vs DRV/r & 2NRTIs) Treatment difference: Treatment Difference: 100 3.8% (95% CI: -2.4% to 100 7.1% (95% CI: 0.5% to 10.0%) 13.7%) 80 77.5 73.6 80 73.1 66.0 60 60

40 40 1 RNA < 50 copies/mL (%) 1 RNA < 50 copies/mL (%) - 20 - 20 HIV HIV 280/ 252/ n/N = 383 383 0 0 DOR/3TC/TDF EFV/FTC/TDF DOR DRV/RTV + + 2 NRTIs 2 NRTIs 1. Orkin. IDWeek 2018. Abstr LB1. 2. Orkin. Clin Infect Dis. 2018;[Epub]. Molina JM, et al. AIDS 2018. Abstract LBPEB017. Doravirine Week 96 data FDA snapshot analyses Drive Ahead (vs EFV/3TC/TDF) Drive Forward (vs DRV/r & 2NRTIs) Treatment difference: Treatment Difference: 100 3.8% (95% CI: -2.4% to 100 7.1% (95% CI: 0.5% to 10.0%) 13.7%) 80 77.5 73.6 80 73.1 66.0 60 60

40 40 1 RNA < 50 copies/mL (%) 1 RNA < 50 copies/mL (%) - 20 - 20 HIV HIV 280/ 252/ n/N = 383 383 0 0 DOR/3TC/TDF EFV/FTC/TDF DOR DRV/RTV + + 2 NRTIs 2 NRTIs 1. Orkin. IDWeek 2018. Abstr LB1. 2. Orkin. Clin Infect Dis. 2018;[Epub]. Molina JM, et al. AIDS 2018. Abstract LBPEB017. Doravirine: naïve, week 96 Safety/resistance data Drive Ahead (vs EFV/3TC/TDF) Drive Forward (vs DRV/r & 2NRTIs) Resistance n=6 (1.6%) DOR vs n=13 Resistance n=2 (0.5%) DOR vs 1 (0.3%) (3.8%) EFV arm DRV/r arm NRTI resistance 1.4% DOR vs 1.6% EFV NRTI resistance DOR only (FTC)

Drug related AEs 32% DOR vs 65% EFV Drug related AEs similar

Fewer neuropsychiatric AEs DOR Favorable lipids profile DOR

LDL-C & non –HDL cholesterol small decreases DOR cf increases in EFV

1. Orkin. IDWeek 2018. Abstr LB1. 2. Orkin. Clin Infect Dis. 2018;[Epub]. Molina JM, et al. AIDS 2018. Abstract LBPEB017. Doravirine: treatment naïve – week 96 data

DOR/3TC/TDF Doravirine

DelstrigoTM PifeltroTM Bictegravir/FTC/TAF: treatment naïve – week 96 data no food requirements, single tablet regimen § GS-1489 n=629 § GS-1490 n=645 § Double blind RCT, phase III § Double blind RCT, phase III § BIC/FTC/TAF vs § BIC/FTC/TAF vs DTG + F/TAF DTG/ABC/3TC § VL ≥500, eGFR ≥30mL/min § VL ≥500, HLA B*5701 neg, § Primary endpoint week 48 eGFR ≥50mL/min 89% vs 93% § Primary endpoint week 48 92.4% vs 93%

1. Wohl. IDWeek 2018. Abstr LB4. 2. Gallant. Lancet. 2017;390:2063. Stellbrink. Glasgow 2018. Abstactr O211. Bictegravir/FTC/TAF: week 96 virological outcomes

§ GS-1489 BIC/F/TAF vs DTG/ABC/3TC § GS-1490 BIC/F/TAF vs DTG + F/TAF

1. Wohl. IDWeek 2018. Abstr LB4. 2. Gallant. Lancet. 2017;390:2063. Stellbrink. Glasgow 2018. Abstactr O211. Bictegravir/FTC/TAF: week 96 virological outcomes

§ GS-1489 BIC/F/TAF vs DTG/ABC/3TC § GS-1490 BIC/F/TAF vs DTG + F/TAF

1. Wohl. IDWeek 2018. Abstr LB4. 2. Gallant. Lancet. 2017;390:2063. Stellbrink. Glasgow 2018. Abstactr O211. Bictegravir/FTC/TAF: treatment naïve – week 96 safety/resistance

GS-1489 BIC/F/TAF vs DTG/ABC/3TC GS-1490 BIC/F/TAF vs DTG + F/TAF No treatment emergent No treatment emergent resistance in either arm resistance in either arm Significantly more Rx Significantly more Rx related related AEs DTG arm (28 vs AEs in DTG arm (20 vs 28%) 40%), mainly nausea No lipid differences BMD similar Greater increases total & LDL-C in BIC arm 1. Wohl. IDWeek 2018. Abstr LB4. 2. Gallant. Lancet. 2017;390:2063. Stellbrink. Glasgow 2018. Abstactr O211. AMBER: DRV/COBI/FTC/TAF vs DRV/COBI + FTC/TDF in Treatment-Naive Adults at Wk 96 § Multicenter, randomized, double-blind, noninferiority phase III trial[1] Primary Analysis Current Analysis Wk 48 Wk 96

Treatment-naive adults with DRV/COBI/FTC/TAF DRV/COBI/FTC/TAF HIV-1 RNA ≥ 1000 copies/mL, (n = 362) (n = 335) CD4+ counts > 50 cells/mm3, Rollover phase DRV/COBI/FTC/TA genetic susceptibility to DRV, DRV/COBI + FTC/TDF Switch to DRV/COBI/FTC/TAF F FTC, TFV, no HBV/HCV infection (n = 363) (n = 295) (N = 725)

§ Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 (noninferiority margin: -10%)[2] ‒ DRV/COBI/FTC/TAF vs DRV/COBI + FTC/TDF: 91.4%vs 88.4%(difference: 2.7%; 95% CI: -1.6% to 7.1%; P < .0001)

1. Orkin. Glasgow 2018. Abstr O212. 2. Eron. AIDS. 2018;32:1431. AMBER (DRV/c/F/TAF vs DRV/c + F/TAF) Efficacy, resistance & safety at wks 96

FDA Snapshot ITT Resistance : 1 patient with M184V/I in 100 88 84 each arm. No emergent DRV, primary PI, or TFV RAMs 80 Less effects on bone, renal markers with 60 DRV/COBI/FTC/TAF 40 No significant change eGFR or cases 20 Fanconis/tubulopathy 1 RNA < 50 copies/mL (%) - Similar lipid changes across arm HIV 0 DRV/c/F/TAF DRV/c & F/TDF

Orkin. Glasgow 2018. Abstr O212. Dual therapy

OR Dual therapy Dual therapy DTG + 3TC vs DTG + TDF/FTC in Treatment-Naive Patients GEMINI-1 and -2 § Parallel, international, randomized, double-blind phase III noninferiority studies

Primary Analysis Wk 48 Wk 144

Continuation of ART-naive adults with HIV-1 RNA DTG + 3TC PO QD DTG + 3TC 1000-500,000 copies/mL, no major (n = 716) permitted resistance associated mutation, no HBV infection (N = 1433) DTG + TDF/FTC PO QD (n = 717)

Primary endpoint: HIV-1 RNA < 50 copies/mL at Week 48 by FDA Snapshot analysis

68% White; 15% women; 10% >50yrs 20% VL>100,000copies/mL; 8-9% CD4 <200 cells/mL

Cahn P, et al. AIDS 2018. Abstract TUAB0106LB. Cahn, Lancet 2018, 393,10167;143-155 GEMINI-1 and -2: Virologic Response at Wk 48

Virologic Outcomes by FDA Snapshot Analysis Adjusted Treatment Difference,† % (95% CI)

DTG + 3TC (n = 716) 100 9193 9394 ITT-E DTG + TDF/FTC (n = 717) DTG + TDF/FTC DTG + 3TC 80 DTG + 3TC (n = 694) PP* DTG + TDF/FTC (n = 693) -1.7 60 ITT-E -4.4 1.1 1 RNA - 40 -1.3 HIV PP* 20 -3.9 1.2 3 2 2 1 6 5 5 4 < 50 copies/mL (%) 0 Virologic Virologic No Virologic -10 -8 -6 -4 -2 0 2 4 6 8 10 Success Nonresponse Data Percentage Difference

Cahn P, et al. AIDS 2018. Abstract TUAB0106LB. Cahn, Lancet 2018, 393,10167;143-155 GEMINI-1 and -2: Virologic Response at Wk 48

Virologic Outcomes by FDA Snapshot Analysis Adjusted Treatment Difference,† % (95% CI)

Cahn P, et al. AIDS 2018. Abstract TUAB0106LB. Cahn, Lancet 2018, 393,10167;143-155 GEMINI-1 and -2: Virologic Response at Wk 48 by Baseline HIV-1 RNA and CD4+ Cell Count Virologic Outcomes by FDA Snapshot Analysis Virologic Outcomes by TRDF Analysis DTG + 3TC DTG + TDF/FTC 98 98 99 97 98 98 98 100 100 91 94 92 90 93 93 93 100 79 80 80 60 60

(%) 40 40 TRDF (%) 1 RNA < 50 c/mL Patients With - 20 20 526/ 531/ 129/ 138/ 605/ 618/ 50/ 51/ 566/ 553/ 138/ 149/ 642/ 647/ 62/ 55/ n/N = Patients Without n/N = 576 564 140 153 653 662 63 55 576 564 140 153 653 662 63 55 HIV 0 ≤ 100,000 > 100,000 > 200 ≤ 200 0 ≤ 100,000> 100,000 > 200 ≤ 200 Baseline HIV-1 Baseline CD4+ Baseline HIV-1 Baseline CD4+ RNA, c/mL Cell Count, cells/mm3 RNA, c/mL Cell Count, cells/mm3 § TRDF includes confirmed virologic withdrawal, withdrawal for lack of efficacy or treatment-related AEs, and participants meeting protocol-defined stopping criteria

Cahn P, et al. AIDS 2018. Abstract TUAB0106LB. Cahn, Lancet 2018, 393,10167;143-155 Details of Nonresponse to DTG + 3TC Among 13 Patients With Baseline CD4+ Cell Count ≤ 200 cells/mm3

Participant[1] Wk 48 Snapshot Outcome Clinical Reason for Study D/c Last Study VL, c/mL 1 VL ≥ 50 c/mL NA, continued in study ≥ 50 (Wk 60) 2 VL ≥ 50 c/mL NA ,continued in study < 50 (Wk 60) 3 VL ≥ 50 c/mL NA, continued in study < 50 (Wk 60) 4 VL ≥ 50 c/mL Protocol-defined virologic withdrawal 362 (d/c Day 205) 9 VL ≥ 50 c/mL NA, unplanned change in ART ≥ 50 (Wk 60) 10 VL ≥ 50 c/mL Protocol violation, randomized in error 102 (d/c Day 15) 12 VL ≥ 50 c/mL Lost to follow-up 64,366 (d/c Day 356) 5 No virologic data AE, pulmonary TB < 50 6 No virologic data AE, cerebral chagoma 507,564 (d/c ART before study d/c) 7 No virologic data Treatment for HCV infection < 50 8 No virologic data Withdrew consent < 50 11 No virologic data Protocol violation, randomized in error 1,848,435 (Day 1 result) Orkin. Glasgow 2018. Abstr P021. Reproduced with permission. 13 No virologic data Lost to follow-up < 50 GEMINI-1 and -2: Safety and Resistance at Wk 48

DTG + DTG + 3TC Safety Event, n (%) TDF/FTC Confirmed VF: dual = 6; triple = 4 (n = 716) (n = 717) Any AE 543 (76) 579 (81) No treatment-emergent INSTI or AE in ≥ 5% of patients NRTI mutations in patients with § Headache 71 (10) 75 (10) VF in either arm § Diarrhea 68 (9) 77 (11) § Nasopharyngitis 55 (8) 78 (11) § Upper RTI 56 (8) 44 (6) Significant benefit in renal § Nausea 27 (4) 53 (7) parameters in dual arm § Insomnia 27 (4) 45 (6) § Pharyngitis 36 (5) 32 (4) § Back pain 35 (5) 31 (4) Significant benefit in bone Drug-related AE 126 (18) 169 (24) parameters in dual arm AE leading to withdrawal 15 (2) 16 (2) § Neuropsychiatric 6 (< 1) 4 (< 1) Any serious AE 50 (7) 55 (8)

Cahn P, et al. AIDS 2018. Abstract TUAB0106LB. Cahn, Lancet 2018, 393,10167;143-155 GEMINI-1 and -2: Viral response & Target Not Detected (TND) analyses Snapshot analysis of % with HIV RNA Target not detected analysis <50 c/mL ITT • Similar proportions in dual/triple arms had TND at snapshot analysis

• No difference in TND rates VL ≤100,000c/mL but numerically higher in DTG/3TC in ≥100,000c (and quicker)

Cahn, Lancet 2018, 393,10167;143-155 Underwood. CROI 2019. P490 EACS 9.1 Oct 2018 Naive

BIC/F/TAF (BiktarvyTM) DRV/c/F/TAF (SymtuzaTM)

www.eacsociety.org/files/2018_guidelines-9.1-english.pdf accessed 12.3.19 EACS 9.1 Oct 2018 Naive

DTG+3TC = alternative

www.eacsociety.org/files/2018_guidelines-9.1-english.pdf accessed 12.3.19 IAS-USA July 2018 NAIVE

BIC/F/TAF

https://www.iasusa.org/wp-content/uploads/guidelines/arv/arv_2018.pdf accessed 12.3.19 IAS-USA July 2018 NAIVE

Dual therapy – only if ABC/TDF/TAF not an option (DRV/r + Ral; DRV/r + 3TC …await Gemini studies…)

https://www.iasusa.org/wp-content/uploads/guidelines/arv/arv_2018.pdf accessed 12.3.19 DHHS May 2018 - naive

BIC/F/TAF

https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/37 accessed 12.3.19 DHHS May 2018 – naïve alternatives

DOR/TDF/3TC (DelstrigoTM)

DTG+3TC

https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/37 accessed 12.3.19 Meet Bob, Sam, Izzy & Ray Bob – been declining Rx, wants new ART, no side effects

Sam – on treatment for years, lots of comorbidities wants to know about switching options

Izzy –fed up of pills, wants to know about injectables

Ray – multidrug resistance, detectable viral load, CD4 declining Switch to DOR/3TC/TDF vs Continuation of Baseline ART in Virologically Suppressed Adults - DRIVE-SHIFT Wk 48 results

Wk 24 Wk 48

Adults with HIV-1 RNA DOR/3TC/TDF* DOR/3TC/TDF* < 40 copies/mL, stable ART for ≥ 6 mos with no (n = 447) (n = 427) prior virologic failure or Baseline ART† DOR/3TC/TDF* resistance to study drugs, and eGFR ≥ 50 mL/min (n = 223) (n = 209) (N = 670)

†2 NRTIs + RTV- or COBI-boosted PI (ATV, DRV, LPV), EVG/COBI, or NNRTI (EFV, NVP, RPV).

§ Primary endpoint: HIV-1 RNA < 50 copies/mL (FDA Snapshot)

Kumar. IDWeek 2018. Abstr LB2. Switch to DOR/3TC/TDF vs Continuation of Baseline ART DRIVE-SHIFT: Wk 48 virological/resistance/safety results

No treatment emergent resistance in DOR arm More TRAEs in DOR (20 vs 2%) 7 (1.6%) d/c due to DOR TRAEs

Significant decreases LDL-C & non-HDL-C in DOR

Kumar. IDWeek 2018. Abstr LB2. Switch to DOR/3TC/TDF vs Continuation of Baseline ART DRIVE-SHIFT: Wk 48 virological/resistance/safety results

No treatment emergent resistance in DOR arm More TRAEs in DOR (20 vs 2%) 7 (1.6%) d/c due to DOR TRAEs

Significant decreases LDL-C & non-HDL-C in DOR

Kumar. IDWeek 2018. Abstr LB2. Switch to DTG + RPV vs Continuation of Baseline ART in Virologically Suppressed Adults: SWORD-1 and -2

Early Switch Phase Late Switch Phase Primary Endpoint Wk 48 Wk 52 Wk 100 Wk 148 (HIV-1 RNA < 50 copies/mL at Wk 100)[2] Adults on stable ART (INSTI, NNRTI, or PI + Switch to DTG + RPV Continue DTG + RPV 89% 2 NRTIs*) with HIV-1 RNA (n = 513) < 50 copies/mL for ≥ 6 mos at screening; no previous VF or Continue Baseline ART current HBV infection Switch to DTG + RPV (n = 511) 93% (N = 1024) DTG dosed 50 mg PO QD; RPV dosed 25 mg PO QD. *70% to 73% of patients receiving TDF at baseline.

§ Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 (noninferiority margin: -8%)[3] § Wk 100: 1% confirmed virologic withdrawal; emergent NNRTI resistance in 3/10, all early switch arm[2]

1. Underwood. Glasgow 2018. Abstr P311. 2. Aboud. AIDS 2018. Abstr THPEB047. 3. Llibre. Lancet. 2018;391:839. Switch to DTG + RPV vs Continuation of Baseline ART : SWORD-1 and -2 Wk 100 results § Target not Detected (TND) data: 3/10 failures had NNRTI resistance; no INSTI resistnace TRAEs: Headache/nausea (2% each) Reduction in markers of bone turnover & renal tubular function No affect on lipids or inflammation markers

1. Underwood. Glasgow 2018. Abstr P311. 2. Aboud. AIDS 2018. Abstr THPEB047. 3. Llibre. Lancet. 2018;391:839. EMERALD: Switch From Suppressive Boosted PI + FTC/TDF to DRV/COBI/FTC/TAF at Wk 96

Wk 48 Wk 96 Primary Analysis Current Analysis Adults with HIV-1 RNA < 50 c/mL while receiving boosted Immediate Switch to DRV/COBI/FTC/TAF† PI* + FTC/TDF; no prior VF on (n = 763) Rollover to DRV; no DRV RAMs if historical Continue Boosted PI DRV/COBI/FTC/TAF genotype known Late Switch to + FTC/TDF (N = 1141) DRV/COBI/FTC/TAF† (n = 378)

.*Eligible boosted PIs: ATV/COBI or RTV, DRV/COBI or RTV, LPV/RTV. †800/150/200/10 mg QD § Primary endpoint: cumulative virologic rebound at Wk 48 (ITT) ‒ Switch to DRV/COBI/FTC/TAF vs continue boosted PI + FTC/TDF: 2.5% vs 2.1%

Eron. IDWeek 2018. Abstr 1768. Orkin. Lancet HIV. 2018;5:e23. EMERALD: Virologic Outcomes & safety in DRV/COBI/FTC/TAF Immediate Switch Arm Through Wk 96 (ITT) FDA Snapshot at Wk 96 No resistance mutations DRV/COBI/FTC/TAF (n = 763) DRV/COBI/FTC/TAF (n = 763) Improvement in bone parameters 95 100 91 Small eGFR decrease to Wk 96 ; other renal markers improved 80 60 Lipids – small but significant increase (8% patients requiring Rx at 40 wk 96 cf 3% at wk48) 20 Patients, % (95% CI*) 0 VL < 50 c/mL

Eron. IDWeek 2018. Abstr 1768 EACS 9.1 Oct 2018 Stable switch

Dual therapies as class sparing strategies – DTG + RPV

www.eacsociety.org/files/2018_guidelines-9.1-english.pdf accessed 12.3.19 IAS-USA July 2018 stable switch

D/C/F/TAF BIC/F/TAF https://www.iasusa.org/wp-content/uploads/guidelines/arv/arv_2018.pdf accessed 23.3.19 IAS-USA July 2018

Dual therapy option in switching: DTG/RPV DTG/3TC

https://www.iasusa.org/wp-content/uploads/guidelines/arv/arv_2018.pdf accessed 12.3.19 Meet Bob, Sam, Izzy & Ray Bob – been declining Rx, wants new ART, no side effects

Sam – on treatment for years, lots of comorbidities wants to know about switching options

Izzy –fed up of pills, wants to know about injectables

Ray – multidrug resistance, detectable viral load, CD4 declining FLAIR Study Design: Randomized, Multicenter, International, Open-Label, Noninferiority Study in ART-Naïve Adults Week 48 O10 Orkin 9.30 Thurs

Screening Induction Phase Phase Maintenance Phase Extension Phase N=809 N=629 DTG/ABC/3TC ART-naïve DTG/ABC/3TC Oral daily n=283 HIV-1 RNA ≥1000 single-tablet Any CD4 count regimen for Oral CAB ‡ HBsAg-negative CAB LA (400 mg) + RPV LA (600 mg) † + RPV Extension 20 weeks IM monthly n=278 NNRTI RAMs excluded* n=283

Study Week −20 −4 Day 1 4§ 48 96 100

Confirm HIV-1 RNA Randomization (1:1) Primary Endpoint <50 copies/mL

Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947. FLAIR Virologic Snapshot Outcomes at Week 48 for ITT-E: Noninferiority Achieved for Primary and Secondary Endpoints

Virologic Outcomes Adjusted Treatment Difference (95% CI)*

CAB LA + RPV LA DTG/ABC/3TC 100 93.6 93.3 Primary endpoint: -0.4 LA noninferior to 80 CAB LA + RPV LA DTG/ABC/3TC (n=283) -2.8 2.1 6% NI (≥50 c/mL) at margin Week 48 60 DTG/ABC/3TC (n=283) -10 -8 -6 -4 -2 0 2 4 6 8 10 Difference (%) 40 DTG/ABC/3TC CAB LA + RPV LA Key secondary

Proportion of Participants (%) 20 0.4 endpoint: LA noninferior to 2.1 2.5 4.2 4.2 -10% NI -3.7 4.5 DTG/ABC/3TC 0 margin (<50 c/mL) at Virologic Virologic No virologic Week 48 nonresponse success data -10 -8 -6 -4 -2 0 2 4 6 8 10 (≥50 c/mL) (<50 c/mL) Difference (%)

• 3 VF in LA arm: all A1, L74I at baseline; maintained susceptibility DTG *Adjusted for sex and baseline HIV-1 RNA (< vs ≥100,000 c/mL). • 3 VF DTG/TDF/3TC arm, no resistance Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947. FLAIR Virologic Snapshot Outcomes at Week 48 for ITT-E: Noninferiority Achieved for Primary and Secondary Endpoints

Virologic Outcomes Adjusted Treatment Difference (95% CI)*

• 3 VF in LA arm: all A1, L74I at baseline; maintained susceptibility DTG *Adjusted for sex and baseline HIV-1 RNA (< vs ≥100,000 c/mL). • 3 VF DTG/TDF/3TC arm, no resistance Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947. ATLAS Study Design: Randomized, Multicenter, International, Open-Label, Noninferiority Study in Adults with Virologic Suppression - week 48 P 012 Screening Phase Maintenance Phase Extension Phase‡ Margolis

† PI-, NNRTI-, or PI, NNRTI or INSTI INSTI-based Current daily oral ART n=308 regimen with Extension Phase or 2 NRTI transition to the 1:1 backbone* ATLAS -2M study Oral CAB + CAB LA (400 mg) + RPV LA (600 mg)§ N=705

Randomization RPV n=308 IM monthly n=303

Day 1 Week 4ǁ Week Week Week Baseline 48 52 96 Primary Endpoint

*†INSTI-based regimen capped at 40% of enrollment; Triumeq excluded from study;

33% Women; 26% > 50yrs; median time on ART 4 yrs (1-21) Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475. ATLAS Virologic Snapshot Outcomes at Week 48 for ITT-E: Primary and Secondary Endpoints

Virologic Outcomes Adjusted Treatment Difference (95% CI)*

CABCAB LA + RPV LA LA + RPV LA CARCAR 100 92.5 95.5 Primary endpoint: CAB LA + RPV LA 0.6 LA noninferior to 80 (n=308) CAR (HIV-1 RNA CAR (n=308) -1.2 2.5 6% NI ≥50 c/mL) at Week 48 margin 60 -10 -8 -6 -4 -2 0 2 4 6 8 10 Difference (%) 40 CAR CAB LA + RPV LA Key secondary 20 endpoint:

Proportion of Participants (%) -3.0 5.8 LA noninferior to 1.6 1.0 3.6 −10% CAR (HIV-1 RNA 0 -6.7 0.7 NI <50 c/mL) at Week 48 Virologic Virologic No virologic margin nonresponse success data -10 -8 -6 -4 -2 0 2 4 6 8 10 (≥50 c/mL) (<50 c/mL) Difference (%)

. *Adjusted for sex and baseline third agent class. Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475. ATLAS Virologic Snapshot Outcomes at Week 48 for ITT-E: Primary and Secondary Endpoints

Virologic Outcomes Adjusted Treatment Difference (95% CI)*

. *Adjusted for sex and baseline third agent class. Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475. ATLAS: Safety (excluding ISRs) & resistance CAB + RPV LA arm 29% TRAES (cf 3% 3 VF in LA arm: all subtype A CAR ). Nausea, headache, fatigue & variety - A/A1 or AG. pyrexia 4%, mostly (95%) grade 1-2. – CAB/RPV resistance in 1 – RPV only resistance in 2. 10 (3%) AEs CAB + RPV LA cf 8 (2%) CAR arm led to withdrawal

No cases of drug-related SAEs, drug hypersensitivity, or drug-induced liver injury observed on CAB LA + RPV LA arm

Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.

ATLAS Injection Site Reactions

ISR Incidence by Week CAB LA + RPV LA N=308 100 Event Participants receiving injections, n 303 80 Injections given, n 6978 ISR events, n (%) 1460 (20.9) 60 Pain 1208 (82.7) Nodule 54 (3.7) 40 Induration 54 (3.7) Swelling 48 (3.3) Participants with ISRs (%) 20 Grade 3 ISR pain 20 (1.7) Median duration of ISRs, days 3 0 Participants with ISR leading to 4B 8 12 16 20 24 28 32 36 40 44 48 4 (1.3) withdrawal, n (%) Study Week

• The majority (99%,1439/1460) of ISRs were grade 1–2 and most (88%) resolved within ≤7 days • 4 withdrawals due to ISR

Bars represent incidence of onset ISRs relative to the most recent IM injection visit. Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475. LATTE-2 : CAB +RPV LA vs oral CAB +ABC/3TC

Induction Maintenance perioda Extension perioda

CAB 400 mg IM + RPV 600 mg IM CAB 400 mg IM + RPV 600 mg IM Q4W (n=115) Q4W (n=115)

CAB CAB loading dose at Day 1 (800 mg) ART- Naïve, 30 mg + CAB 600 mg IM + RPV 900 mg IM CAB 600 mg IM + RPV 900 mg IM ABC/3TC Q8W (n=115) Q8W (n=115) CD4≥200 for cells/mm3, no 20 wk CAB loading doses at Day 1 (800 mg) and Week 4 (600 mg) Q4W Optimized loading dose CAB 600 mg IM + RPV 900 mg IM (Week 100) resistance followed by 400 mg + 600 mg IM Q4W (n=10) CAB 30 mg + ABC/3TC PO QD (n= 56)b N=309 Q8W Optimized loading dose Add RPV CAB 600 mg IM + RPV 900 mg IM (Weeks 100 & 104) PO QD followed by Q8W (n=34)

4 wk Day 1 Week 32 Week 48 Week 96b Week 160 Randomization Primary Analysis 2:2:1 analysis Dosing Dosing regimen regimen selection confirmation Primary endpoints: HIV-1 RNA < 50 copies/mL (FDA Snapshot), PDVF, safety at maintenance Wk 32[2] 94% in Q4W arm (difference vs oral treatment: 2.8%; 95% CI: -5.8% to 11.5%), 95% in Q8W arm (difference vs oral treatment: 3.7%; 95% CI: -4.8% to 12.2%), 91% in oral treatment arm

PDVF in 1% by Wk 96; ISRs mild (84%) or moderate (15%), led to d/c in < 1% of patients Margolis et al. HIV Glasgow; Glasgow, UK. Poster 118. Latte-2 Outcomes Randomized and Nonrandomized Switch Arms: Week 160 HIV-1 RNA <50 c/mL (ITT-ME)

Virologic outcomes PDVF in 2 patients (1% )by wk 48; no PDVF after week 48 97 100 100 90 CAB + RPV LA Q8W (n=115) 83 ISRs mild (84%) or moderate (15%), led 80 CAB + RPV LA Q4W (n=115) to d/c in < 1% of patients

60 Optimized CAB + RPV LA Q8W TRAEs: (n=34) Randomized arms: pyrexia (5%), 40 Optimized CAB + RPV LA Q4W headache (3%), fatigue (3%) (n=10)

Participants, % Participants, Optimized arms: (all 2%) asthenia, 17 20 fatigue, palpitations 4 5 0 3 0 0 0 0 HIV-1 RNA <50 HIV-1 RNA ≥50 No virologic c/mL c/mL data

Margolis et al. HIV Glasgow; Glasgow, UK. Poster 118. Meet Bob, Sam, Izzy & Ray Bob – been declining Rx, wants new ART, no side effects

Sam – on treatment for years, lots of comorbidities wants to know about switching options

Izzy –fed up of pills, wants to know about injectables

Ray – multidrug resistance, detectable viral load, CD4 declining DTG or LPV/RTV + 2NRTIs as Second-line ART: DAWNING • International, randomized, open-label phase IIIb noninferiority study

Stratified by number of fully active NRTIs Primary Endpoint (2 vs < 2), HIV-1 RNA (≤ vs > 100,000 c/mL) Wk 48 Wk 52

Patients with HIV infection and VF (2 instances of DTG + 2 NRTIs* HIV-1 RNA ≥ 400 copies/mL) on first-line NNRTI + 2 DTG + 2 NRTIs NRTIs; receiving first-line regimen (n = 312) continuation ≥ 6 mos; no primary resistance to INSTIs or PIs † (N = 624) LPV/RTV + 2 NRTIs* phase (n = 312)

*Investigator-selected NRTIs; included ≥ 1 fully active NRTI according to HIV genotypic resistance testing at screening.

Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 by FDA Snapshot algorithm with noninferiority margin of 12%

Brown. CROI 2019. Abstr 144. Aboud. Lancet Infect Dis. 2019;19:253 DAWNING: Virologic Response & resistance data at Wk 48 Virologic Outcomes DTG + 2 NRTIs 100 LPV/RTV + 2 NRTIs 84 87

(%) 80 74 70

40 1 RNA < 50 c/mL -

HIV 20 261/ 219/ 246/ 204/ n/N = 219/ 312 312 283 312274 0 ITT-E PP

Brown. CROI 2019. Abstr 144. Aboud. Lancet Infect Dis. 2019;19:253 DAWNING: Virologic Response & resistance data at Wk 48 Virologic Outcomes DTG + 2 NRTIs Post-hoc analysis 100 LPV/RTV + 2 NRTIs 87 HIV-1 RNA < 50 copies/mL at Wk 84 48: (%) 80 74 70 • In patients with BL M184V/I 60 ± other NRTI RAMs receiving 3TC or FTC: 85% 40 • In patients with K65R 1 RNA < 50 c/mL - receiving TDF: 86%

HIV 20 261/ 219/ 246/ 204/ n/N = 219/ • In patients with ≥ 1 TAM 312 312 283 312274 0 receiving ZDV: 86% ITT-E PP

Brown. CROI 2019. Abstr 144. Aboud. Lancet Infect Dis. 2019;19:253 BRIGHTE: Fostemsavir in Heavily Treatment– Experienced Adults at Wk 48

Randomised Cohort §: Blinded FTR 600 mg HTE participants failing current BID + failing regimen with confirmed HIV-1 RNA ≥ Randomised regimen Open Label FTR 600 mg BID + OBT 400 c/mL and: 3:1 Blinded placebo + • 1 or 2 ARV classes remaining & ≥1 failing fully active & available agent per regimen class Day 8 – Day 9 – End of • Day 1 Unable to construct viable Week 24* Week 48* Week 96* † regimen from remaining agents Primary Open Label Study Endpoint FTR + OBT Non-randomised Cohort §: HTE participants, failing current regimen with confirmed HIV-1 RNA ≥ Non-randomised Open Label FTR 600 mg BID + OBT 400 c/mL and: • 0 ARV classes remaining and no End of remaining fully active approved Day 1 Week 24 Week 48 Week 96 † agents‡ Study

Aberg et al. HIV Glasgow 2018; Glasgow, UK. Oral 334A. BRIGHTE: fostemsavir efficacy & safety at Wk 48

Efficacy at wk 48 (FDA snapshot) Median CD4 increase:

80 3 69 127 cells/mm randomisedarm 70 Randomised cohort 3 60 54 53 Non randomised cohort 35 cells/mm non-randomised 50 43 38 38 40

% patients 30 22 Generally well tolerated 20 9 10 0 35%/44% had SAE Treatment related SAEs 3%

Aberg J, et al. Glasgow 2018. Abstract O344A. IBALIZUMAB Long acting monoclonal antibody CD4 directed post attachment HIV-1 inhibitor n=40; inclusion: 3 drug resistance, Wk 25 (1o endpoint) – 43% HIV RNA >1,000c/mL HIV RNA <40 ITT Wk 48: All 15 with HIV RNA IBA IV every 2 weeks + OBR (=incl 1 <50c/ml at wk 25 maintained active drug) Wk 96 : Safety & efficacy of IBA 9/10 VF/rebound had decreased maintained susceptibility IBA Licensed USA 2018 Most common AE diarrhea

Emu, NEJM 2018 379;645-654 Cohen, Glasgow 2018 Abs O345 Emu, CROI 2019 Abs 485. EACS 9.1 Oct 2018 Resistance

DTG + 2NRTIs (if ≥1 NRTI active) alternative to DRV/r

www.eacsociety.org/files/2018_guidelines-9.1-english.pdf accessed 12.3.19 IAS-USA July 2018

DTG & 2NRTIs: option if NNRTI failure (if ≥ active NRTI)

https://www.iasusa.org/wp- content/uploads/guidelines/arv/arv_2018.pdf accessed 12.3.19 IAS-USA July 2018

Ibalizumab in multiclass resistance https://www.iasusa.org/wp-content/uploads/guidelines/arv/arv_2018.pdf accessed 12.3.19 with 1 other active drug Pipeline • Leronlimab (PRO 140): (CROI poster 486) – Phase IIb/III, weekly subcut, single agent maintenance • GSK 2838232 maturation inhibitor (CROI oral abs 142) – Phase IIa, oral daily with COBI • GS-6207 Capsid inhibitor (CROI oral abs 141) – Phase I , subcut • PGT 121 mAB (CROI oral abs 145) – Phase I IV/Subcut. Resistance in all rebounds http://www.croiwebcasts.org/y/2019/7?link=nav&linkc=date Bob, Sam, Izzy & Ray Bob – BIC/F/TAF or DOR/TDF/3TC….DTG/3TC?

Sam – DOR/TDF/3TC or DRV/c/F/TAF or dual DTG/RPV

Izzy –…CAB/RPV 2020?

Ray – DTG +2NRTIs or Ibalizumab or Fostemsavir? Thanks for listening

Questions?

Thanks to Yvonne Gilleece BHIVA due soon…?

https://www.bhiva.org/HIV-1-treatment-guidelines Accessed 13.3.19