The Integrase Inhibitor Drug Class: A Comparative Clinical Review

The Integrase Inhibitor Drug Class: A Comparative Clinical Review Ian Frank Professor of Medicine University of Pennsylvania Philadelphia, PA USA franki@pennmedicine.upenn.edu

Disclosure Gilead, ViiV/GlaxoSmithKline: Advisory board membership Janssen: Research support

Outline Discuss some advantages of integrase inhibitors vs other classes of agents and differences among drugs within the class Discuss some of the classic studies with the current integrase inhibitors in naïve and experienced patients Discuss some of newer data and provocative studies with drugs in this class

Mechanism of Action of Integrase Strand Transfer Inhibitors

DHHS, IAS-USA Guidelines: Recommended Regimens for First-line ART Class DHHS [1] IAS-USA [2] INSTI BIC/TAF/FTC DTG/ABC/3TC DTG + (TAF or TDF)/FTC EVG/COBI/(TAF or TDF)/FTC RAL + (TAF or TDF)/FTC BIC/TAF/FTC DTG/ABC/3TC DTG + TAF/FTC Recommendations may differ based on baseline HIV-1 RNA, CD4+ cell count, CrCl, egfr, HLA-B*5701 status, HBsAg status, osteoporosis status, and pregnancy status Data are lacking for women of child-bearing age not using contraception IAS-USA now lists EVG/COBI/TAF/FTC and RAL + TAF/FTC as alternative regimens owing to their lower resistance barriers and, respectively, more drug interactions and higher pill burden [2] 1. DHHS Guidelines. May 2018. 2. Saag MS, et al. JAMA. 2018;320:379-396.

WHO Guidelines Updated Summary of Sequencing Options for First-, Second- and Third-Line Art Regimens for Adults (Including Pregnant Women and Adolescents) and Children Population First-Line Regimens Second-Line Regimens Third-Line Regimens Adults and adolescents (including women and adolescent girls who are of childbearing potential women or pregnant) Two NRTIs + DTG Two NRTIs + EFV Two NRTIs + (ATV/r or lopinavir/ritonavir (LPV/r) Two NRTIs + DTG Darunavir/ritonavir (DRV/r) + DTG i + 1-2 NRTIs (if possible, consider optimization using genotyping) Children Two NRTIs + DTG Two NRTIs + (ATV/r or LPV/r) Two NRTIs + LPV/r Two NRTIs + NNRTI Two NRTIs + DRG Two NRTIs + DTG http://www.who.int/hiv/pub/guidelines/en/ (accessed 7/25/18)

Why do the Guidelines Prefer the Integrase Inhibitors? Integrase inhibitors Protease inhibitors (DRV, ATV) Potency Potent (more) Potent Potent Time to suppression Fastest Not bad Not bad Resistance Convenience Tolerability / toxicity Low genetic barrier (1 st generation) High genetic barrier (2 nd generation) Once daily No food restrictions (except EVG/c) Well tolerated Neural tube defects in pregnancy? (DTG) High genetic barrier when boosted Once daily Taken with food GI intolerance Hyperbilirubinemia (ATV) Metabolic effects None CV risk, hyperlipidemia, increases bone toxicity of TDF Drug-drug interactions Few Many, need the booster Some NNRTIs (EFV) Low genetic barrier Once daily Taken at bedtime CNS intolerance, depression, suicidality Hyperlipidemia

Comparative Effectiveness of First-Line ARV regimens in Brazil Objective: Estimate the rates of virologic suppression in Brazilians starting antiretroviral therapy using different combinations. Ministry of Health Database Started therapy January 2014 to June 2017 Had a follow-up viral load 180 days (+/- 90 days) from baseline 103,240 were included in the analyses Population Characteristics Age: 34 (26-43) 67.6% were male CD4: 394 (209-581) cells/mm 3 VL: 38,057 copies/ml Adherence: 96.2% (82.4%-100.0%) Overall, 76.9% achieved a 6-month VL 50 copies/ml Meireles MV, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0101.

Comparative effectiveness of first-line ARV regimens in Brazil Regimens and Rate of VL Suppression Multivariable analysis % VS (%) aor 95% CI Regimen 3TC+TDF+DTG 7.2 85.2 1.42 (1.32-1.52) 3TC+TDF+EFV 74.0 78.0 1 3TC+AZT+LPV/r 4.9 67.2 0.59 (0.55-0.63) 3TC+TDF+ATV/r 4.6 71.3 0.67 (0.63-0.72) 3TC+AZT+EFV 3.5 72.9 0.94 (0.87-1.02) 3TC+TDF+LPV/r 2.0 63.7 0.54 (0.49-0.60) Others 3.7 67.9 0.67 (0.62-0.73) Conclusion: Highest rate of virologic suppression with integrase inhibitors Meireles MV, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0101.

Structure of Integrase Inhibitors Raltegravir Elvitegravir Dolutegravir Binds Mg++ in integrase Bictegravir Cabotegravir Binds to hydrophobic pocket in integrase

Advantages and Disadvantages of HIV Integrase Inhibitors Raltegravir Elvitegravir/cobic istat Dolutegravir Potency Potent Potent Potent Potent Resistance Low genetic barrier Low genetic barrier Convenience Two tablets Only available as co-formulation Tolerability / toxicity Drug-drug interactions Cost (AWP/mo) in US www.goodrx.com Rare CPK elevation Few Increase in creatinine Many, due to booster High barrier Active against virus resistant to 1 st generation Once daily Increase in creatinine insomnia /CNS intolerance Few $1667 $3306 (Genvoya) $1842 $3430 (Triumeq) Bictegravir High barrier Active, but not useable against virus resistant to 1 st generation Only available as co-formulation Increase in creatinine Few $3520 (Biktarvy)

INSIGHTFUL TRIALS and COHORT STUDIES

Dolutegravir Efficacy in ART-Naïve Patients Regimen < 50 c/ml, n/n (%) PDFV n (%) Randomized, Noninferiority Phase III Studies in ART-Naïve Patients Primary Endpoint: HIV-1 RNA <50 c/ml at Week 48 DTG + 2 NRTI 332/411 (81%) SPRING-2 (Wk 96) RAL + 2 NRTI 314/411 (76%) DTG + ABC/3TC 331/414 (80%) SINGLE (Wk 96) EFV/TDF/F TC 203/419 (72%) DTG + 2 NRTI 194/242 (80%) FLAMINGO (Wk 96) DRV/r + 2 NRTI 164/242 (68%) 22 (5%) 29 (7%) 25 (6%) 25 (6%) 0 0 DTG was non-inferior to RAL in SPRING-2 DTG demonstrated superiority to EFV/TDF/FTC (SINGLE) and DRV/r (FLAMINGO) No treatment-emergent resistance to DTG through 96 wks in SPRING-2, SINGLE, and FLAMINGO PDFV = protocol-defined virologic failure. Raffi F, et al. Lancet Infect Dis. 2013;13(11):927-935; Walmsley S, et al. CROI 2014. March 3-6, 2014, Boston, MA. Abstract 543; Molina JM, et al. Lancet. 2015;2(4):e127-e136.

Proportion of Patients SINGLE (DTG + ABC/3TC) vs EFV/TDF/FTC: Virologic Suppression <50 copies/ml 100 90 DTG + ABC/3TC QD EFV/TDF/FTC QD DTG: 80% 80 70 60 50 40 30 20 10 0 0 CD4 from BL 4 8 12 16 Week 96 adjusted difference in response (95% CI): +8.0% (+2.3% to +13.8%); P=0.006 Treatment Wk96 from BL Adjusted mean EFV: 72% 24 32 40 48 60 72 84 96 SE DTG + ABC/3TC QD (n=414) 325.3 10.5 EFV/TDF/FTC QD (n=419) 281.4 10.9 Difference in response (95% CI) 44.0 (14.3, 73.6) P=0.004 Week Walmsley S, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 543.

SINGLE (DTG + ABC/3TC) vs EFV/TDF/FTC: Resistance Mutations Individuals Who Met Protocol Defined Virologic Failure Criteria Mutation DTG + ABC/3TC QD (n=414) EFV/TDF/FTC QD (n=419) NRTI TE Major Mutations 0 1 (K65R) NNRTI TE Major Mutations 0 6 (K101E, K103N, G190A) INI-r TE Major Substitution 0 0 Walmsley S, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 543.

Proportion (Percentage) FLAMINGO Study (DTG vs DRV/r): HIV RNA <50 c/ml 100% 90% No Emerging Resistance in Any Group DTG:90% 80% 70% 60% 50% 40% 30% 20% 10% 0% DTG 50 mg QD DRV/r 800 mg/100 mg QD BL 4 8 12 16 24 36 48 Weeks 95% CI for Difference DRV/r:83% Favors DRV/r Favors DTG 0.9 7.1 13.2-20% -12% 0% 20% Test for superiority: P=0.025 Results confirmed in per protocol analysis: 91% DTG versus 84% DRV/r, Δ (CI): 7.4 (1.4-13.3) Clotet B, et al. 14th EACS; Brussels, Belgium; October 16-19, 2013. Abst. LBPS4/6.

FLAMINGO Study: Outcomes by Viral Load and NRTIs Favors DRV/r Favors DTG DTG DRV/r Baseline 100,000 c/ml ABC/3TC at Day 1 TDF/FTC at Day 1 n=134 n=228 89% 88% 88% 86% Baseline >100,000 c/ml ABC/3TC at Day 1 TDF/FTC at Day 1 n=25 n=97-20 -10 0 10 20 30 40 50 60 92% 94% 67% 71% Difference in proportion (DTG- DRV/r; unadjusted) DTG showed superiority in high viral load and comparable efficacy independent of NRTI backbone through all VL strata Clotet B, et al. 14th EACS; Brussels, Belgium; October 16-19, 2013. Abst. LBPS4/6.

DAWNING Study: DTG vs LPV/r in second-line therapy Open-Label Randomised Noninferiority Phase IIIb Study Open label, randomised 1:1 DTG + 2 NRTIs LPV/RTV + 2 NRTIs DTG + 2 NRTIs Continuation phase Randomisation Week 24 interim analysis Week 48 primary analysis Week 52 Eligibility criteria: on first-line 2 NRTIs + NNRTI regimen for 6 months, failing virologically (HIV-1 RNA 400 c/ml on 2 occasions); no primary viral resistance to PIs or INSTIs; at least 1 active NRTI Stratification: by HIV-1 RNA ( or >100,000 copies/ml), number of fully active NRTIs in the investigator-selected study background regimen (2 or <2) Primary endpoint: proportion with HIV-1 RNA <50 c/ml at Week 48 using the FDA snapshot algorithm (12% noninferiority margin) Aboud M, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. THPEB040.

HIV-1 RNA < 50 c/ml, % DAWNING Study: Virologic Outcomes at Week 48 Virologic outcomes Treatment differences (95% CI) 100 80 60 40 20 0 84 261/ 312 70 219/ 312 87 246/ 283 74 204/ 274 Virologic success DTG + 2 NRTIs (ITT-E, n=312) LPV/r + 2 NRTIs (ITT-E, n=312) DTG + 2 NRTIs (PP, n=283) LPV/r + 2 NRTIs (PP, n=274) LPV/r DTG 13.8 ITT-E 7.3 20.3 12.3 PP 5.8 18.7-12 -8-4 0 4 8 12 16 20 24 Proportion of participants with HIV-1 RNA <50 c/ml at Week 48: DTG 84% vs LPV/r 70%; treatment difference [95% CI], 13.8% [7.3%-20.3%]; P<0.001 for superiority) Virologic nonresponse at week 48: DTG 30 (10%) LPV/r 68 (22%) Aboud M, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. THPEB040.

HIV-1 RNA < 50 c/ml, % DAWNING STUDY: Treatment Response by Sub-group 100 80 60 84 Treatment Response by Subgroups 89 84 84 70 71 64 65 59 73 80 69 88 72 40 20 0 Overall 100,000 > 100,000 2 < 2 < 200 < 200 Baseline VL Active Drugs CD4+ Count DTG + 2 NRTIs LPV/r + 2 NRTIs Aboud M, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. THPEB040.

Dawning Study: Emergent Resistance Mutations Confirmed virologic withdrawal criteria any time DTG 10 (3%), LPV/r 28 (9%) Resistance Analysis DTG + 2 NRTIs (n=8) LPV/RTV + 2 NRTIs (n=24) INSTI 0 0 NRTI 0 3 K70R 0 2 M184V 0 1 K219Q 0 1 K219E 0 1 PI 0 0 Aboud M, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. TUAB0105LB.

SAILING Study: DTG vs RAL after treatment failure Design HIV ART-experienced, INI-naive HIV-1 RNA >400 c/ml a 1:1 Randomization stratified by HIV-1 RNA ( or >50,000), DRV/r use and # of fully active drugs DTG 50 mg QD + RAL PBO + BR RAL 400 mg BID + DTG PBO + BR Randomization Week 24 planned interim Week 48 primary analysis BR, background regimen comprising at least 1 and no more than 2 active agents.

Percentage of subjects (%) SAILING Study: DTG vs RAL Primary Endpoint: HIV-1 RNA <50 c/ml at Week 48 80 60 71 64 95% CI for difference Favors RAL Favors DTG 40 20 20 28 9 9 0.7 7.4 14.2 0 Virologic success Virologic nonresponse No W48 data* DTG 50 mg QD (n=354) RAL 400 mg BID (n=361) -20% -12% 0 20%

SAILING Study: DTG vs RAL Protocol-Defined Virologic Failure Fewer PDVFs for DTG versus RAL by Week 48 DTG 50 mg QD (N=354) RAL 400 mg BID (N=361) Week 16 10 (3%) 21 (6%) Virologic non-response 0 13 (4%) Rebound 10 (3%) 8 (2%) Week 24 15 (4%) 35 (10%) Virologic non-response 1 (<1%) 19 (5%) Rebound 14 (4%) 16 (4%) Week 48 21 (6%) 45 (12%) Virologic non-response 2 (<1%) 19 (5%) Rebound 19 (5%) 26 (7%)

DTGFC at Baseline Impact of INSTI Mutations on Dolutegravir Susceptibility 40 20 10 6 4 2 1 0.6 Stay tuned for Charles Boucher s presentation IN Mutation Pathway at Baseline DTG 50 mg QD DTG 50 mg BID Q148 + 2 Mixture Q148 + 1 N155 Y143 Other IN Mutations Subjects, n Cohort I 3 2 4 4 12 2 Cohort II 2 1 8 6 6 1 DTG fold change at baseline in Viking by Integrase mutational Pathway Eron et al JID 2013

GS-1489 Study (B/F/TAF vs DTG/ABC/3TC): Study Design and Baseline Characteristics Treatment-Naïve Adults HIV-1 RNA 500 copies/ml egfr CG 50 ml/min HLA B*5701 negative Negative for chronic HBV Gallant J, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. MOAB0105LB. B/F/TAF n=314 26 DTG/ABC/3TC n=315 Age, median years (range) 31 (18 71) 32 (18 68) Male, % 91 90 Race/ethnicity, % 1:1 n=314 n=315 Primary Endpoint Week 0 48 96 144 B/F/TAF QD DTG/ABC/3TC Placebo QD DTG/ABC/3TC QD B/F/TAF Placebo QD Black or African descent 36 36 Hispanic/Latino ethnicity 23 21 HIV-1 RNA, median log 10 c/ml (IQR) 4.42 (4.03, 4.87) 4.51 (4.04, 4.87) HIV-1 RNA >100,000 c/ml, % 17 16 CD4 cell count, median cells/µl (IQR) 443 (299, 590) 450 (324, 608) CD4 count <200 cells/µl, % 11 10 Asymptomatic HIV infection, % 91 91 egfr CG, median ml/min (IQR) 126 (108, 146) 123 (107, 144)

HIV-1 RNA <50 c/ml, % GS-1489 Study (B/F/TAF vs DTG/ABC/3TC): Results 100 80 92,4 Virologic Outcome 93 B/F/TAF (n=314) DTG/ABC/3TC (n=315) % Treatment Difference (95% CI) Favors DTG/ABC/3TC Favors B/F/TAF 60 40-0.6-4.8 3.6 20 0 HIV-1 RNA <50 copies/ml 290 293 314 315 1 HIV-1 RNA 50 copies/ml 3 8 314 315 6,7 2,5 4,4 No Virologic Data 21 314 14 315-12 -8-4 0 4 8 12 BF-TAF non-inferior to DTG/ABC/3TC No resistance in either study arm Lipids not significantly different No drug-related renal events Significantly less nausea and minor adverse events with B/F/TAF Gallant J, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. MOAB0105LB.

GS-1490 Study (B/F/TAF vs DTG + F/TAF): Study Design and Baseline Characteristics Primary Endpoint Week 0 48 96 144 Treatment-Naïve Adults HIV-1 RNA 500 copies/ml 1:1 n=320 B/F/TAF QD DTG + F/TAF Placebo QD egfr CG 30 ml/min n=325 DTG + F/TAF QD B/F/TAF Placebo QD Sax P, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. TUPDB0201LB. B/F/TAF (n=320) DTG + F/TAF (n=325) Median age, y (range) 33 (18 71) 34 (18 77) Male, % 88 89 Race/ethnicity, % Black or African descent 30 31 Hispanic/Latino 26 25 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, % 21 17 Median CD4 cell count, cells/µl (Q1, Q3) 440 (289, 591) 441 (297, 597) CD4 count <200 cells/µl, % 14 10 HBV*/HCV coinfection, % 3/2 2/2 Median egfr CG, ml/min (Q1, Q3) 120.4 (100.8, 141.8) 120.6 (102.8, 145.1) 28

HIV-1 RNA <50 c/ml, % GS-1490 Study (B/F/TAF vs DTG + F/TAF): Results 100 80 89 93 99 Virologic Outcome >99 B/F/TAF DTG + F/TAF 1 PP % Treatment Difference (95% CI) Favors DTG + F/TAF Favors B/F/TAF 60 40 20 0 4 6 6 1 1 <1 0 0 HIV-1 RNA HIV-1 RNA No Virologic 1 PP -3.5-7.9 1.0-0.7-2.6 1.2-12 0 12 286 302 279 296 320 325 282 297 14 320 4 325 3 282 1 297 Bictegravir non-inferior to dolutegravir Results consistent in sensitivity analyses No integrase resistance No difference in nausea Sax P, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. TUPDB0201LB. 20 320 19 325 0 282 14 297

Mean change from baseline (SD) in serum creatinine, mg/dl SINGLE (DTG + ABC/3TC vs EFV + TDF/FTC): Creatinine Profile Over Time DTG + ABC/3TC EFV + TDF/FTC 0.3 0.2 0.1 0 0.1 No. of patients DTG + ABC/3TC EFV + TDF/FTC 0.2 BL 4 12 24 32 40 48 60 72 84 96 108 120 132 144 399 399 391 387 379 367 369 359 355 350 344 336 332 322 312 390 390 375 363 352 345 342 330 317 311 308 300 288 282 267 Parameter Urine albumin/ creatinine ratio (mg/mmol) DTG + ABC/3TC QD EFV + TDF/FTC QD Week 48 Week 96 Week 144 Week 48 Week 96 Week 144 0 0 0 0.05 0.05 0.10 Median change (IQR) (-0.3, 0.3) (-0.3, 0.2) (-0.4, 0.2) (-0.2, 0.3) (-0.2, 0.3) (-0.2, 0.4) Pappa K, et al. 54th ICAAC; Washington, DC; September 5-9, 2014; Abst. H-647a.

Patient Percent DTG Discontinuation in Clinical Practice 387 patients started DTG (65 naïve) (median CD4 650/mm 3 ) 16% stopped after a median of 78 days (range 5-327), 20% of naïves Reason 35% 30% 25% 20% 15% 10% 5% 0% Stopped DTG alone Stopped ABC/3TC/DTG Sleep problems GI problem Psychiatric Headache Fatigue Van der Berk G, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 948.

DTG and Neural Tube Defects Stay tuned for Rebecca Zash s 0.94 presentation now being given by Mauro Schechter 0.12 0 0.09 No. of Infants with Defect 4 14 0 61 No. of Exposures 426 11,300 2812 66,054 Percent with Defect 0.84 0.12 0.0 0.09 (95% CI) (0.37 to 2.4) (0.07 to 0.21) (0.0 to 0.13) (0.07 to 0.12) Difference in Prevalence Reference 0.82 0.94 0.85 (95% CI) Percentage Points ( 0.24 to 2.3) ( 0.35 to 2.4) ( 0.27 to 2.3) Zash R et al. NEnglJMed 2018: July 24.

NEWER DATA AND INTERESTING CONCEPTS

GEMINI 1 and 2: Study design Screening (28 d) 1:1 Double-blind phase Open-label phase Continuation phase ART-naive adults VL 1000-500,000 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 resistance-associated mutation No HBV infection or need for HCV therapy Cahn P, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0106LB.

HIV-1 RNA <50 c/ml, % GEMINI 1 and 2: Snapshot Outcomes at Week 48 Virologic outcome Adjusted treatment difference (95% CI) a GEMINI-1 DTG + 3TC (N=356) DTG + TDF/FTC (N=358) GEMINI-2 DTG + 3TC (N=360) DTG + TDF/FTC (N=359) 100 93 90 93 94 80 DTG DTG + TDF/FTC + TDF/FTC DTG + 3TC 60 GEMINI-1-2.6 40 20 0 Virologic success 4 6 6 5 2 2 2 4 Virologic nonresponse No virologic data -6.7 1.5 GEMINI-2-0.7-4.3 2.9 Percentage-point difference Cahn P, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0106LB.

HIV-1 RNA <50 c/ml, % GEMINI 1 and 2: Results Snapshot Analysis by Visit: Pooled ITT-E Population 100 80 60 72 70 87 89 85 89 88 90 93 93 91 93 90 91 DTG + 3TC (n=716) DTG + TDF/FTC (n=717) 40 20 0 0-20 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 Study week Cahn P, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0106LB.

GEMINI 1 and 2: Pooled Outcomes at Week 48 Snapshot Analysis TRDF Analysis 526 576 531 564 129 140 138 153 605 653 618 662 50 63 51 55 566 576 553 564 138 140 149 153 642 653 647 662 62 63 55 55 100,000 >100,000 >200 200 Baseline HIV-1 RNA, c/ml Baseline CD4+ cell count, cell/mm 3 100,000 >100,000 >200 200 Baseline HIV-1 RNA, c/ml Baseline CD4+ cell count, cell/mm 3 DTG + 3TC DTG + TDF/FTC 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 P, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0106LB.

GEMINI 1 and 2: Results Low rates of virologic withdrawals were observed at Week 48 No resistance mutations 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 0 0 0 0 0 0 Cahn P, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0106LB.

Patients (%) ASPIRE Trial: Phase 2 Study of Dolutegravir + Lamivudine for Maintenance Therapy Virologic Outcomes (FDA Snapshot) Dolutegravir + lamivudine provided comparable maintenance of viral suppression Rare viral blips (n=1) Virologic failure (n=1 in each arm) No emergence of resistance at virologic failure CD4 gain was similar between the 2 arms Both regimens were well tolerated over 48 weeks Discontinuation due to adverse events (n=1, dual therapy) Similar changes in total cholesterol, LDL- C, triglycerides, and creatinine clearance Fully powered randomized trial ongoing TANGO studies 100 80 60 40 20 0 Dolutegravir + lamivudine (n=44) Continue triple therapy (n=45) 2% 0% Week 24 Week 48 Virologic Failure 2% 2% Difference (%): 2.1 (-11.2, 15.3) 93% 91% Difference (%): 2.0 (-12.6, 16.5) 91% 89% Week 24 Week 48 HIV RNA <50 Copies/mL Taiwo B, et al. Clin Infect Dis. 2018;66:1794-1797.

SWORD: Dolutegravir + Rilpivirine for Maintenance of Suppression Phase III, Randomized, Multicenter, Open-label, Parallel-Group, Non-Inferiority Studies Screening Early Switch Phase a Late Switch Phase Continuation Phase VL <50 c/ml on INI, NNRTI, or PI + 2 NRTIs 1:1 DTG + RPV (N=513) CAR (N=511) DTG + RPV DTG + RPV Day 1 Week 52 Week 148 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-1RNA <50 c/ml during the 12 months before screening Primary endpoints at 48 weeks: subjects with VL <50 c/ml (ITT-E snapshot) b a. DTG + RPV once daily or 2 NRTIs + INI/PI/NNRTI (CAR). b. 90% power based on 10% non-inferiority margin (estimated response rate =87%). Countries Argentina France Russia United States Australia Germany Spain Belgium Italy Taiwan Canada Netherlands United Kingdom Llibre J, et al. 24th CROI; Seattle, WA; February 13-16, 2017. Abst. 44LB.

HIV-1 RNA <50 c/ml, % SWORD: DTG + RPV for Maintenance of Suppression: Outcomes at Week 48 Adjusted Treatment Difference (95% CI) 100 95 Virologic Outcomes ITT-e (Pooled) 95 CAR DTG + RPV 90 80 70 DTG + RPV (n=513) CAR (n=511) -0.2 60 50 40 30 20-3.0 2.5 10 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 DTG+RPV is non-inferior to CAR with respect to snapshot in the ITT-E population (<50 c/ml) at Week 48 Llibre J, et al. 24th CROI; Seattle, WA; February 13-16, 2017. Abst. 44LB.

LATTE-2: Study Design Induction period Maintenance period CAB 400 mg IM + RPV 600 mg IM Q4W (n=115) CAB 30 mg + ABC/3TC for 20 weeks CAB loading dose at Day 1 (800 mg) CAB 600 mg IM + RPV 900 mg IM Q8W (n=115) CAB loading doses at Day 1 (800 mg) and Week 4 (600 mg) CAB 30 mg + ABC/3TC PO QD (n=56) Add RPV PO QD 4 weeks Day 1 Randomization 2:2:1 Week 32 Primary analysis Dosing regimen selection Week 48 Analysis Dosing regimen confirmation Week 96 Eron J, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. MOAX0205LB.

HIV-1 RNA <50c/mL, % LATTE-2 Study: Efficacy Virologic Outcomes Treatment Differences (95% CI) 100 80 94 87 84 CAB + RPV LA Q8W (n=115) CAB + RPV LA Q4W (n=115) CAB + NRTIs PO (n=56) Oral Q8W IM IM 10.0% 60-0.6 20.5-12 -9-6 -3 0 3 6 9 12 15 40 Q4W IM 20 13 14 0 Virologic Success 4 0 2 Virologic Non-Response 2 No Virologic Data -8.4 14.4-12 -9-6 -3 0 3 6 9 12 15 Eron J, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. MOAX0205LB.

INSPIRING study: Phase IIIb, DTG vs EFV in HIV-Tb Co-infection Phase IIIb, randomized, multicenter, open-label, non-comparative, active-controlled, parallel-group study TB therapy HRZE (2 months) HR (4 months) a DTG dose switch 2 weeks post-completion of TB treatment HIV/TB co-infected ART-naive adults DTG (50 mg BID) + 2 NRTIs (n=69) EFV (600 mg QD) + 2 NRTIs (n=44) DTG (50 mg QD) + 2 NRTIs Screening 28 to 14 days Day 1 Inclusion criteria HIV-1 RNA 1000 copies/ml and CD4+ 50 cells/mm 3 Pulmonary, pleural, or lymph node tuberculosis with RIF-sensitive MTB confirmed by culture or GeneXpert RIF-containing TB treatment started up to a maximum of 8 weeks before randomization and no later than the screening date 24 weeks Interim analysis: % <50 copies/ml (modified Snapshot) 52 weeks End of randomized phase Primary endpoint at Week 48: % <50 copies/ml (modified Snapshot) DTG:EFV 3:2 randomization stratified by Screening plasma HIV-1 RNA 100,000 or >100,000 copies/ml Screening CD4+ 100 or >100 cells/mm3 Continuation Phase (ART) aduration of continuation phase of TB treatment according to local guidelines (up to 7 months in some countries Dooley K, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0206.

Participants, % (95% CI) INSPIRING study: DTG vs EFV in HIV-Tb Co-infection FDA Snapshot Outcomes at Week 48 100 80 75 82 DTG ITT-E (n=69) EFV ITT-E (n=44) n (%) Virologic success (HIV-1 RNA <50 copies/ml) DTG (n=69) EFV (n=44) 52 (75) 36 (82) 60 40 Virologic nonresponse 6 (9) 3 (7) Data in window not <50 copies/ml Discontinued for other reason while not <50 copies/ml 0 2 (5) 6 (9) a 1 (2) b Change in ART 0 0 20 0 Virologic success 9 7 Virologic non-response 16 11 No virologic data Dooley K, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0206. No virologic data 11 (16) 5 (11) Discontinued because of AE or death 0 2 (5) c Discontinued for other reasons 11 (16) d 3 (7) e Missing data during window but on study 0 0 a DTG: discontinued for other reasons while not <50 copies/ml: 3 lost to follow-up; 2 withdrawal of consent; 1 pregnancy. b EFV: discontinued for other reasons while not <50 copies/ml: 1 lost to follow-up. c EFV: discontinued due to AE: 1 EFV hypersensitivity; 1 increased gamma-glutamyltransferase. d DTG: No virologic data/discontinued for other reasons: 7 lost to follow-up; 2 pregnancies; 1 physician decision; 1 withdrawal of consent. eefv : No virologic data/discontinued for other reasons: 2 lost to follow-up; 1 withdrawal of consent (patient relocated).

INSPIRING study: TB- and Non TB-Associated Immune Reconstitution Inflammatory Syndrome (IRIS) n (%) Participants with events sent to adjudication committee for TB-associated IRIS Met criteria for TB-associated IRIS Possibly met criteria for TB-associated IRIS Participants with events sent to adjudication committee for non TB-associated IRIS Met criteria for non TB-associated IRIS Possibly met criteria for non TB-associated IRIS DTG (n=69) 9 (13) 4 (6) a 0 2 (3) 1 (1) c 1 (1) d No participant in either arm permanently discontinued treatment because of IRIS Treatment outcomes EFV (n=44) 12 (27) 4 (9) b 0 3 (7) 0 0 n (%) DTG (n=69) EFV (n=44) Treatment Success 61 (88) 40 (91) Treatment failure 0 1 (2) Died 0 0 Not evaluated / Lost to follow-up 8 (12) 3 (7) a 1 Grade 1, 2 Grade 2, and 1 Grade 3. b 3 Grade 2 and 1 Grade 4. c Grade 2 (IRIS and strongyloidiasis; also experienced TB-associated IRIS). d Grade 1 (herpes zoster). Dooley K, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0206.

Conclusions Integrase inhibitors have transformed the treatment landscape We have excellent drugs in the class (some are more excellent than others) A lot more to come