Comparison of Current International Guidelines for Treatment-Naive Pts

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1 Comparison of Current International Guidelines for Treatment-Naive Pts Regimen DHHS [1] EACS [2] BHIVA [3] IAS-USA [4] GeSIDA [5] EFV/TDF/FTC RPV/TDF/FTC ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC DTG/ABC/3TC DTG + TDF/FTC EVG/COBI/TDF/FTC RAL + TDF/FTC Preferred/recommended Alternative 1. DHHS Guidelines. April EACS HIV Guidelines. V 8.0. October BHIVA Guidelines Günthard H, et al. JAMA. 2014;312: GeSIDA. Enferm Infecc Microbiol Clin. 2013;31:602.e1-e602.

2 Antiretrovirals available in 2016 NRTIs Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine NNRTIs Delavirdine Efavirenz Etravirine Nevirapine Nevirapine XR Rilpivirine PIs Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir Integrase Inhibitors Raltegravir Dolutegravir Elvitegravir Fusion Inhibitors Enfuvirtide Entry Inhibitors Maraviroc PK Boosters Ritonavir Cobicistat Single Pill Regimens Atripla Eviplera Stribild Triumeq Genvoya NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; PK, pharmacokinetic Adapted from

3 Antiretrovirals available in 2016 NNRTIs Delavirdine Efavirenz Etravirine Nevirapine Nevirapine XR Rilpivirine PIs Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir Integrase Inhibitors Raltegravir Dolutegravir Elvitegravir Fusion Inhibitors Enfuvirtide Entry Inhibitors Maraviroc PK Boosters Ritonavir Cobicistat NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; PK, pharmacokinetic Adapted from

4 Can we live without nucleosides? NAÏVE THE JURY IS STILL OUT SWITCH PROBABLY WE CAN SALVAGE. YES WE CAN clinicaloptions.com/hi v

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6 millions Cost of treating 20,000 people with triple combination treatment versus DRV/r monotherapy over three years UK: DRV/r monotherapy budget impact Gazzard 6 et al., EACS 2011 Belgrade PE million Before switching to DRV/r monotherapy Cost saving 163 million 248 million After switching to DRV/r monotherapy

7 Options NRTI

8 Options NNRTI NRTI

9 Options NNRTI NRTI II

10 Options NNRTI NRTI II PI

11 J Lundgren & DAD Study Group et al C NRTIs and risk of MI: recent* and cumulative exposure RR yes/no 95%CI ** RR per year 95%CI ZDV ddi ddc d4t 3TC ABC TDF #PYFU: 138,109 74,407 29,676 95, ,009 53,300 39,157 #MI: * recent use= current or within the last 6 months **: not shown (low number of 0.6

12 FDA Meta-Analysis No Association Between ABC and MI 26 RCTs involving ABC 5028 subjects on ABC, 4840 controls Average 1.62 person/years of F/U Overall events/subjects: 28/5628 ABC vs. 22/4840 controls (OR %CI 0.56, 1.84) Authors conclude that the findings raise significant uncertainty about the likelihood of an ABC-MI risk association Forest Plot of Meta Analysis Results: Trials Sorted Based on Duration of Person Years of Follow-up Study ABC Non-ABC Non-ABC Worse ABC Worse Risk Difference (95% CI) ACTG 368 xii 0/140 (0%) 0/143 (0%) 0 (-2.73, 2.87) COL /58 (0%) 0/29 (0%) 0(-13.79, 6.38) ACTG 372A xiii 4/116 (3.45%) 3/113 (2.65%) 0.79 (-4.77, 6.54) ACTG A5202 xiv 2/923 (0.22%) 5/925 (0.54%) (-1.08, 0.33) ABCDE xv 0/115 (0%) 2/122 (1.64%) (-6.17, 1.64) FIRST xvi 0/93 (0%) 0/89 (0%) 0(-4.49, 4.13) ACTG 5095 xvii 6/758 (0.79%) 1/376 (0.27%) 0.53 (-0.75, 1.5) ACTG A5110 xviii 0/48 (0%) 0/53 (0%) 0 (-7.01, 8.34) STEAL xix 4/178 (2.25%) 1/175 (0.57%) 1.68 (-1.27, 5.17) NEFA xx 1/149 (0.67%) 0/311 (0%) 0.67 (-0.55, 4.04) CNAF3007 1/96 (1.04%) 1/91 (1.1%) (-5.23, 4.9) CNA /80 (0%) 2/127 (1.57%) (-5.61, 3.38) ESS /51 (0%) 0/44 (0%) 0 (-9.09, 7.08) CNAA3006 0/102 (0%) 0/103 (0%) 0 (-3.79, 3.88) NZTA4002 0/150 (0%) 3/152 (1.97%) (-5.94, 0.58) CNA /192 (0%) 1/193 (0.52%) (-3.12, 1.55) CNAB3014 0/165 (0%) 0/164 (0%) 0 (-2.42, 2.4) ESS /85 (1.18%) 0/166 (0%) 1.18 (-1.14, 7.08) BIOCOMBO xxi 1/167 (0.6%) 1/166 (0.6%) 0 (-3.15, 3.11) CNAB3002 0/91 (0%) 0/93 (0%) 0 (-4.35, 4.19) EPZ /343 (0.29%) 0/345 (0%) 0.29 (0.86, 1.75) CNA /324 (0.31%) 0/325 (0%) 0.31 (0.91, 1.86) CNAC3005 1/262 (0.38%) 0/264 (0%) 0.38 (-1.13, 2.29) ESS /137 (0%) 1/141 (0.71%) (-4.27, 2.21) CNAC3003 1/156 (0.54%) 0/80 (0%) 0.64 (-4.21, 3.6) CNAB3001 0/49 (0%) 1/50 (2%) -2(-11.05, 5.37) Mantel-Haenszel 0.01 (-0.26, 0.27) -5.0% -2.5% 0.0% 2.5% 5.0% Ding X, et al. 18th CROI; Boston, MA; February 27-March 2, Abst. 808.

13 INTRODUCING TAF: HOW TAF WORKS GI tract TFV (Tenofovir) TDF (Tenofovir disoproxil fumarate) 300 mg PRO-DRUG TAF (Tenofovir alafenamide fumarate) 25 mg Renal tubular cell Plasma Short plasma half-life Animation for illustrative purposes only. Components not to scale 91% lower plasma TFV Renal tubular cell TFV TFV OAT 1 & 3 Long plasma half-life greater plasma stability OAT 1 & 3 TFV Lymphocyte TFV TFV-DP T 1/2 based on in vitro plasma data/tdf = 0.4 minutes, TAF = 90 min GENVOYA contains a novel prodrug, tenofovir alafenamide (TAF), delivering statistically significant differences in renal and bone parameters vs E/C/F/TDF with a >90% reduction of tenofovir in the plasma 6 8 Favourable changes in markers of proximal renal tubular dysfunction and BMD (hip and spine) at 48 weeks vs TDF-based regimens 6 8 GI, gastrointestinal; OAT, organic anion transporter; E/C/F/TDF, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate; TFV-DP, tenofovir diphosphate; BMD, bone mineral density 1. Lee W, et al. Antimicr Agents Chemo 2005;49: ; 2. Birkus G, et al. Antimicr Agents Chemo 2007;51:543 50; 3. Babusis D, et al. Mol Pharm 2013;10:459 66; 4. Ruane P, et al. J Acquir Immune Defic Syndr 2013;63: ; 5. Sax P, et al. J Acquir Immune Defic Syndr 2014;67:52 8; 6. Sax PE, et al. Lancet 2015;381: SmPC GENVOYA. Available at: 8. Gupta SK, et al. IAS Vancouver, Canada. Oral TUAB0103 Home Going beyond undetectable Back to backbone Introducing TAF Clinical benefits for patients

14 Median change from baseline (Q1,Q3), % Studies 104 and 111: ART-naive patients, Week 48 combined analysis Changes in spine and hip BMD through Week 48 Spine Hip % % 2.86% 2.95% P<0.001* - 6 P<0.001* Weeks Weeks E/C/F/TAF n= E/C/F/TDF n= *Comparison of E/C/F/TAF vs E/C/F/TDF at Week 48 Significantly less decreases in spine and hip BMD in the E/C/F/TAF group at Week 48 BMD = bone mineral density Sax P et al. Lancet Jun 27;385(9987):

15 Median change from BL in egfr CG, (Q1, Q3) ml/min Studies 104 and 111: ART-naive patients, Week 48 combined analysis Changes in egfr (Cockcroft-Gault) through Week E /C /F /T A F 1 0 S t r ib ild P< T im e (W e e k s ) Less GFR decrease with E/C/F/TAF compared to E/C/F/TDF (p<0.001) Pattern of early decline (2 weeks) then stable egfr is consistent with cobicistat inhibition of tubular secretion of creatinine Sax P et al. Lancet Jun 27;385(9987):

16 NRTI-sparing regimens Regimen DRV/r + RAL (ACTG ) DRV/r + RAL (NEAT 2 ) DRV/r + MVC (MODERN 3 ) ATV/r + RAL (HARNESS 4 switch) LPV/r + RAL (PROGRESS 5 ) Results Poor performance at high VL Less effective at high VL, low CD4 Less effective than standard ART Less effective than standard ART Small study; few pts with high VL 1. Taiwo B, et al. AIDS. 2011;25: Raffi et al. CROI 2014, Abstract 84LB 3. Stellbrink H-J, et al. IAD Abstract MOAB Van Lunzen J et al. IAC Abstract A Reynes J, et al. AIDS Res Hum Retroviruses. 2013;29: Daar ES et al. Ann Intern Med 2011; 5;154: Cahn P, et al. Lancet Infect Dis 2014;14: Gatell J, et al. AIDS Abstract LBPE Perez-Molina, J.A., et al. IAC AbstractL BPE18

17 Dual therapy: PI + INSTI vs triple therapy NEAT 001 study design HIV-1 ART-naive 18 years HIV-1 RNA > 1000 copies/ml CD4 500/mm 3 HBs Ag negative No major IAS USA resistance mutations DRV+r mg QD + RAL 400 mg BID Week 96 DRV+r mg QD + TDF/FTC FDC QD Phase III, randomised, open-label, multicentre, parallel-group, non-inferiority, strategic trial 78 sites, 15 countries (Austria, Belgium, Denmark, France, Germany, Great Britain, Greece, Hungary, Ireland, Italy, The Netherlands, Poland, Portugal, Spain, Sweden) Composite virologic and clinical primary endpoint (6 components) Raffi et al. CROI 2014, Abstract 84LB.

18 Dual therapy: PI + INSTI vs triple therapy NEAT 001 primary endpoint Primary endpoint: time to failure 1.00 RAL + DRV/r TDF/FTC + DRV/r Estimated proportion reaching primary endpoint at Week 96 RAL: 17.4% vs TDF/FTC: 13.7% Adjusted difference: 3.7% (95% CI: -1.1 to 8.6) log rank p = N at risk Time (weeks) Raffi et al. CROI 2014, Abstract 84LB.

19 Dual therapy: PI + INSTI vs triple therapy NEAT 001 stratification RAL + DRV/r TDF/FTC + DRV/r Overall n = % 13.7% Baseline HIV-1 RNA < 100,000 copies/ml n = % 7% 100,000 copies/ml n = % 27% p = 0.09* Baseline CD4+ < 200/mm 3 n = % 21.3% 200/mm 3 n = % 12.2% p = 0.02* *Test for homogeneity Raffi et al. CROI 2014, Abstract 84LB Difference in estimated proportion (95% CI) RAL TDF/FTC; adjusted

20 Proportion of subjects with HIV-1 RNA <50 copies/ml HIV-1 RNA <50 copies/ml Over Time TDF/FTC 86.8% 348/401 subjects MVC 77.3% 306/396 subjects Adjusted treatment difference (95% CI): -9.5% (-14.8%, -4.2%) BL Week Mean CD4+ cell count changes at Week 48 (mean ± SD, cells/mm 3 ) MVC + DRV/r ± TDF/FTC + DRV/r ± Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101.

21 PI OT Design Primary Endpoint: Loss of future drug options, defined as: new intermediate/high level resistance to 1 drug to which the patient s virus was considered to be sensitive at trial entry Patton et al. CROI 2014 poster 550

22 PI OT Outcomes Patton et al. CROI 2014 poster 550

23 MODAt Study: switch to ATV/r monotherapy Efficacy results HIV RNA < 50 c/ml at W48 (ITT) Confirmed virologic rebound % ATV/r + 2 NRTI ATV/r Re-intensification Re-intensification = failure = success Sub groups ATV/r + 2 NRTI N = 52 ATV/r N = 51 N 2 11 HIV RNA pre-art > 100,000 c/ml 1 6 Nadir CD4 < 350/mm HCV co-infection / 52 37/ 51 (95% CI) ( ; 3.6) 44/ 52 47/ 51 (95% CI) 7.5 (- 4.7 ; 19.8) Emergence of R mutations 1 (NRTI) 0 Predictor of treatment failure in the ATV/r arm : HCV co-infection (HR : 7.64 ; 95% CI: 1.44 to 40.47, p = 0.017) MODAT Castagna A. AIDS 2014;28:

24 Monotherapy: maintenance therapy for treatmentexperienced patients? Lower chance of maintaining viral suppression when switched to PI/r monotherapy 1,2 Clinical consequences? 1,2 Risk ratios for maintaining viral suppression for PI monotherapy vs cart at 48 weeks follow-up (ITT analysis, viral suppression < 50 copies/ml) 1 LPV/r (Arribas 2005) LPV/r (Pulido 2007) SAQ/r (Echeverria 2008) LPV/r (Waters 2008) LPV/r (Cahn 2009) LPV/r (Gutmann 2010) LPV/r (Meynard 2010) RR (95% CI) % Weight 0.85 (0.68, 1.07) (0.85, 1.05) (0.58, 1.05) (0.69, 1.26) (0.96, 1.43) (0.59, 0.95) (0.85, 1.07) DRV/r (Arribas 2010) DRV/r (Katlama 2010) Overall (I-squared = 30.7%, p = 0.173) 0.99 (0.89, 1.10) (0.86, 1.03) (0.89, 1.00) Favours cart Favours PI monotherapy SAQ, saquinavir 1. Mathis S, et al. PLoS ONE 2011;6:e Bierman WF, et al. AIDS. 2009;23:

25 HARNESS Study: switch to ATV/r + RAL Design Randomisation 2 : 1 Open-label W24 W48 Adults Stable 2 NRTI + 3 rd drug regimen No previous treatment failure HIV RNA < 40 c/ml > 3 months Switch for safety and/or tolerability issues No resistance to study medications HBs Ag negative N = 37 N = 72 ATV/r 300/100 mg qd + TDF/FTC ATV/r 300/100 mg qd + RAL 400 mg bid Objective Primary Endpoint: proportion with treatment success at W24 (HIV-1 RNA < 40 c/ml) No power calculation Descriptive analysis HARNESS Van Lunzen J. JAIDS 2016;71:538-43

26 HARNESS Study: switch to ATV/r + RAL Time to treatment failure (discontinuation of study therapy before W48 or virologic rebound before or at W48) Kaplan-Meier estimate 100 % ATV/r + TDF/FTC ATV/r + RAL Number of patients at risk 0 ATV/r + RAL ATV/r + TDF/FTC B/L Week HARNESS Van Lunzen J. JAIDS 2016;71:538-43

27 HARNESS Study: switch to ATV/r + RAL Efficacy and Safety results HIV RNA < 40 c/ml (ITT) Confirmed virologic rebound at W48, N ATV/r + TDF/FTC % W24 (primary endpoint) 80.6 ATV/r + RAL W ATV/r + TDF/FTC ATV/r + RAL N 1 9 Tested isolates 0 5 PI resistance INI resistance * 1 patient with both PI and INSTI mutations Virologic rebound 1* L10V, G16Q, L33F, P39Q, M46L, G48V, Q58E, I62V, L63I/T, I64L, A71V, I72V, V77I, V82A, T91S, I93L 2* F21Y Y143C + N155H 2 consecutive on-treatment HIV RNA > 40 c/ml Last on-treatment HIV RNA > 40 c/ml followed by discontinuation HARNESS Van Lunzen J. IAC 2014, Melbourne, Abs. LBPE19, Van Lunzen J. JAIDS 2016;71:538-43

28 MARCH: background and study design maraviroc, a CCR5-antagonist, is an appealing switch option in those with R5-tropic virus, as it appears lipid neutral, well tolerated, and may have additional anti-inflammatory properties. Patient population HIV-1-infected aged 18 yrs; 2N(t)RTI + PI/r >24 wks; pvl <200 cp/ml for >24 wks; no known resistance; R5 tropic determined by proviral DNA (in triplicate; FPR cut-off 10%) Randomisation 1:2:2 of eligible patients Arm I: no change 1/5 ( 76) Arm II: replace PI/r with MVC 2/5 ( 152) Arm III: replace N(t)RTI with MVC 2/5 ( 152) Primary endpoint: comparison of proportions of participants with pvl <200 cp/ml 48 weeks after randomisation between the control arm and each switch arm. Switch arms judged non-inferior to control arm if the lower limit of the 95% CI for the difference in virological response between each experimental arm and the control arm did not extend below -12%.

29 MARCH: primary endpoint at week 48 Intention to treat Arm Below threshold (%) Difference (%) <200 cp/ml* Control 97.6 Reference 95% CI Noncompletion=failure Per protocol MVC+2N(t)RTI (-9.0, 2.2) MVC+PI/r (-19.8, -5.8) <200 cp/ml* Control 96.3 Reference MVC+2N(t)RTI (-14.1, -0.4) MVC+PI/r (-23.1, -7.6) <200 cp/ml* Control 98.8 Reference *results from <50 cp/ml were consistent MVC+2N(t)RTI (-3.8, 4.4) MVC+PI/r (-14.2, -2.1)

30 Second-line: LPV/RTV + RAL VS LPV/RTV + NRTIs after first-line virological failure Randomized, open-label, international, multicenter trial Stratified by clinical site, baseline HIV-1 RNA ( or > 100,000 copies/ml) Week 48 primary endpoint HIV-infected pts with virological failure on firstline regimen of 2 NRTIs + NNRTI (N=541) Lopinavir / ritonavir 400/100 mg BID + raltegravir 400 mg BID (n=270) Lopinavir / ritonavir 400/100 mg BID NRTIs QD or BID (n=271) BID, twice daily; QD, once daily Humphries A et al. CROI Abstract 180LB

31 Patients (%) Second-line study: results HIV RNA <200 copies/ml (ITT) 82.6 ( ) 80.8 ( ) P= LPV/r + 2-3N(t)RTI LPV/r + RAL Week Boyd M et al. 20th CROI; Atlanta, GA; March 3 6, Abst. 180LB.

32 Methods (1): EARNEST Trial design HIV positive adolescents / adults 1 st line NNRTI-based regimen >12 months; Failure by WHO (2010) clinical, CD4 (VL-confirmed) or VL criteria RANDOMIZE PI* NRTIs (NRTIs according to local standard of care) PI + RAL FOLLOW-UP FOR 144 WEEKS PI + RAL (12 wk induction) PI (monotherapy) Visits: 1-2 monthly, mainly nurse-led Adherence: assessed at all visits by structured questions; intensive counselling Monitoring: Clinical + CD4 count every weeks (open) VL annually in batch results seen only by Data Monitoring Committee *PI standardized to LPV/r all arms NRTIs physician-selected without resistance testing Paton et al, NEJM 2014; 371:

33 Percent with VL<400 copies/ml VL responses by randomized arm 100 PI/NRTI PI mono PI/RAL Global p< PI/RAL vs PI/NRTI global p< PI-mono vs PI/NRTI global p< Weeks from switch to second-line Week 96 outcomes: Paton, NEJM 2014; 371; ; Week 144 outcomes: Hakim, Poster 552, CROI

34 Percent with VL<400 copies/ml VL response by GSS of NRTIs in the regimen % 89%, 89% 83% 81% 73% Weeks from switch to second-line Global p< Within PI+NRTIs global p=0.007 PI + 0 GSS (N>86) PI GSS (N>59) PI + RAL (N>280) PI GSS (N>140) PI + 2+ GSS (N>21) PI Monotherapy (N>374)

35 OPTIONS: NRTIs versus no NRTIs in highly ARTexperienced patients Randomized, noninferiority, multicentre trial (ACTG A5241) Primary endpoint: regimen failure (VF or divergence from NRTI assignment, whichever occurred first) Stratified by choice of MVC-containing regimen and previous enfuvirtide or integrase inhibitor experience Year 1 Primary endpoint Year 2 Secondary endpoint Treatment-experienced patients failing on PI-based regimen with NRTI, NNRTI experience and / or resistance (N=360) NRTI-omitting Individualized optimized regimen* (n=179) NRTI-including Individualized optimized regimen* (n=181) * 20 potential 3-to 4-drug combinations including DRV/r, ENF, ETV, MVC, RAL, TPV/r. Individualized selection of regimens with PSS >2. ENF, enfuvirtide; MVC, maraviroc; PSS, Phenotypic Susceptibility Score; TPV, tipranavir Tashima K et al. CROI 2013;abstract 153LB

36 OPTIONS: Patient-specific regimen selected prior to randomization Chosen regimens and NRTI combinations 7% 6% 12% 6% 82% Add NRTIs TDF + FTC (3TC) AZT + TDF + FTC (3TC) Other 8% 9% 56% Randomization Add NRTIs 14% Regimen RAL + DRV/r + ETV RAL + DRV/r + MVC RAL + DRV /r + ETV + maraviroc RAL + ETV + maraviroc RAL + DRV/r + ETV + ENF Other Omit NRTIs Tashima K et al. CROI 2013;abstract 153LB. Graphic used with permission.

37 OPTIONS: Omitting NRTIs is noninferior to adding NRTIs to optimized regimen Similar virological suppression (HIV-1 RNA <50 copies/ml) in each arm (~ 65%) Similar CD4+ cell count increases in each arm ( cells/mm 3 ) No significant difference in any safety outcome when globally evaluating symptoms and laboratory abnormalities However, mortality significantly higher in NRTI-added arm (P<0.001) 6 deaths in NRTI arm, 2 possibly due to ART drug Primary efficacy outcome comparisons Outcome, n (%) Regimen failure VF Stop NRTI assignment Omit NRTIs (n=179) 53 (30) 44 (25) 19 (8) Add NRTIs (n=181) 48 (26) 45 (25) 10 (6) Omitting NRTIs Not Inferior Inferior % difference (Omit Add) at 1 Year (95% CI) 3.2 ( 6.1 to 12.5) 0.4 ( 9.4 to 8.7) 3.6 ( 1.7 to 9.0) CI, confidence interval Tashima K et al. CROI 2013;abstract 153LB. Graphic used with permission.

38 Proportion with HIV-1 RNA <50 c/ml (%) VIROLOGIC RESPONSE AT WEEK 96 95% CI for difference Favours Favours DRV/r DTG % 0% 25% Test for superiority: p=0.002 DTG : 80% DRV/r : 68% BL Week Differences largely driven by lower virologic failure rate and fewer withdrawals due to AEs in the DTG arm plus 2 NRTIs DTG 50 mg QD DRV/r 800/100 mg QD Molina JM, et al. HIV Drug Therapy Glasgow Abstract O153

39 Percent survival Risk of virologic rebound according to regimen class 990 (13.0%) patients experienced virologic rebound (CV >50 copies/ml X2) N= Log rank test < INSTI NNRTI PI N at risk: PI INSTI NNRTI Time to viral rebound (month) Allavena C. et al. EACS 2015, Abs. PS 10/1

40 LATTE Study : cabotegravir Phase II Design Phase IIb ARV-naïve HIV RNA > 1,000 c/ml CD4 200/mm 3 Randomisation* 1 : 1 : 1 : 1 Partial-blind (CAB dose) Oral induction 2 NRTI** + CAB 10 mg QD 2 NRTI** + CAB 30 mg QD 2 NRTI** + CAB 60 mg QD Oral maintenance (if HIV RNA < 50 c/ml at W20) RPV 25 mg + CAB 10 mg QD RPV 25 mg + CAB 30 mg QD RPV 25 mg + CAB 60 mg QD 2 NRTI** + EFV 600 mg QD D1 W24 W48 W96 * Randomisation stratified by HIV RNA ( or > 100,000 c/ml) at screening and NRTI backbone ** NRTI backbone (TDF/FTC or ABC/3TC if exclusion of the HLA-B*5701 allele) selected by investigator Objective Primary endpoint : % HIV-1 RNA < 50 c/ml at W48 (FDA snapshot) LATTE Study Intent-to-treat exposed (ITT-E) : received 1 dose of investigational product Intent-to-treat maintenance exposed (ITT-ME) : received 1 maintenance dose Margolis DA. Lancet Margolis Infect D, CROI Dis 2015; 2014, 15: Abs. 91LB

41 LATTE Study : cabotegravir Phase II HIV RNA < 50 c/ml (ITT-E, snapshot) Induction Maintenance % 100 CAB overall 87% CAB overall 82% CAB overall 76% EFV = 74% EFV = 71% weeks CAB 10 mg (N = 60) CAB 30 mg (N = 60) CAB 60 mg (N = 61) EFV 600 mg (N = 62) LATTE Study Margolis DA. Lancet Infect Dis 2015; 15:

42 Cabotegravir + Rilpivirine as Long-Acting Maintenance Therapy: LATTE-2 Week 32 Results David A. Margolis, 1 Juan Gonzalez-Garcia, 2 Hans-Jürgen Stellbrink, 3 Joe Eron, 4 Yazdan Yazdanpanah, 5 Sandy K. Griffith, 1 David Dorey, 6 Kimberly Y. Smith, 1 Peter E. Williams, 7 William R. Spreen 1 1 ViiV Healthcare, Research Triangle Park, NC; 2 Hospital La Paz, Madrid, Spain; 3 ICH Hamburg, Germany; 4 University of North Carolina, Chapel Hill, NC; 5 Hôpital Bichat Claude Bernard, Paris, France; 6 GlaxoSmithKiline, Mississauga, Ontario, Canada; 7 Janssen Research and Development, Beerse, Belgium

43 LATTE-2 Study Design Induction period Maintenance period a CAB 30 mg + ABC/3TC for 20 weeks CAB loading dose at Day 1 CAB 400 mg IM + RPV 600 mg IM Q4W (n=115) CAB 600 mg IM + RPV 900 mg IM Q8W (n=115) CAB loading doses at Day 1 and Week 4 CAB 30 mg + ABC/3TC PO QD (n=56) Day 1 Randomization 2:2:1 Week 32 Primary analysis Dosing regimen selection Week 48 Analysis Dosing regimen confirmation Week 96 b ABC/3TC, abacavir/lamivudine; IM, intramuscular; PO, orally; Q4W, every 4 weeks; Q8W, every 8 weeks; QD, once daily. a Subjects who withdrew after at least 1 IM dose entered the long-term follow-up period. b Subjects can elect to enter LA Extension Phase beyond Week 96. Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.

44 LATTE-2 Week 32 Results: HIV-1 RNA <50 c/ml by Snapshot (ITT-ME) Proportion of patients with virological suppression, % Snapshot success: D1 Q4W 99% Q8W 95% Oral CAB 98% 0 BL W-16 W-12 W-8 W-4 D1 W4 W8 W12 W16 W20 W24 W28 W32 Study visit Margolis et al. CROI 2016; Boston, MA. Abstract 31LB. 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

45 LATTE-2 Week 32 Primary Endpoint: HIV-1 RNA <50 c/ml by Snapshot (ITT-ME) Virologic outcomes Treatment differences (95% CI) * * Oral IM Q8W Q4W Both Q8W and Q4W comparable to oral CAB at Week 32 *Met pre-specified threshold for concluding IM regimen is comparable to oral regimen (Bayesian posterior probability >90% that true IM response rate is no worse than -10% compared with the oral regimen). Margolis et al. CROI 2016; Boston, MA. Abstract 31LB. 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

46 Patient-Reported Outcomes at Week 32: Maintenance Treatment Compared With Oral Induction Treatment a How satisfied are you with your current treatment? 1% 3% 3% 2% How satisfied would you be to continue with your present form of treatment? 1% 1% Note: based on observed case dataset of subjects who completed Week 32 questionnaires. a HIV Treatment Satisfaction Questionnaire change version (HIVTSQc). Margolis et al. CROI 2016; Boston, MA. Abstract 31LB. 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

47 Switch From Suppressive ART to Dolutegravir Monotherapy Single-arm, 24-wk pilot study Primary endpoint: HIV-1 RNA < 37 c/ml at Wk 24 (ITT, NC=F) Eligibility: HIV-1 RNA < 50 c/ml on ART for 12 mos Switched to DTG 50 mg QD monotherapy if 2 of the following: ART or ARTcomorbidity toxicity, avoidance of DDIs, or potential loss of virologic control due to archived resistance Baseline ART: PI (67%), NNRTI (27%), INSTI (6%) Rojas J, et al. EACS Abstract Reproduced with permission. Reasons for Switch, % Underlying cause Pts (N = 33) Comorbidities 97 DDIs 85 ART-related AEs 76 Resistance 48 Immediate cause DDIs 39 GI symptoms 33 Dyslipidemia 27 Osteoporosis 18 High CVD risk 12 CKD progression 3

48 Switch From Suppressive ART to Dolutegravir Monotherapy 97% of pts maintained virologic suppression at Wk 24 [1] Reasons for switch improved in most pts from BL to 24 wks [1] Reason for Switch Pts at Risk, n Outcome Improved/Avoided, n DDIs GI symptoms In separate study of switch from suppressive 11 ART to DTG monotherapy, 9 89% of pts maintained virologic suppression 24 wks after switch [2] Dyslipidemia 9 9 High Framingham score Rojas J, et al. EACS Abstract Katlama C, et al. EACS Abstract 714.

49 Dolutegravir Monotherapy in HIV-infected Patients with Sustained Viral Suppression: A 24-week Pilot Study Post-hoc ultrasensitive viral load analysis Viral load <37 copies/ml were categorized as: negative PCR result positive PCR signal, but <37 copies/ml P= Baseline Week 24 Negative Positive

50 Virological Efficacy at W24 Proportion of patients with HIV RNA <50 cp/ml MonoDTG 28 pts 100% 25/28 VL <50 cp/ml All <50 cp/ml All <20 cp/ml except 37 cp/ml (1) 1 blip W4 (52 cp/ml) 90% 80% 70% 60% 50% 40% 100% CI 95%: % CI 95%: % CI 95%: % CI 95%: virological failures W12: 1 pt VL 138/469 cp/ml W24: 2 pts VL: 2220 cp/ml VL: 291 cp/ml 30% 20% 10% 0% W4 n=23 W8 n=22 W12 n=28 W24 n=28 Katlama C, et al. EACS 2015, Oral PS4/4

51 Efficacy Toxicity Adherence Resistance Drug interactions Cost

52

53 Options 3TC

54 Study design Phase III, randomized, international, controlled, open-label study. Study included adult patients from Argentina, Chile, Mexico, Spain, US. Stratified by screening HIV-1 RNA ( or > 100,000 copies/ml) Wk 24 interim analysis Wk 48 primary endpoint ARV- naïve patients, 18 years HIV-1 RNA >1,000 copies/ml No IAS-USA defined NRTI or PI resistance at screening* HB(s)Ag negative (n: 426) DT: LPV/r 400/100mg BID + 3TC 150 mg BID (n: 217) TT: LPV/r 400/100mg BID+ 3TC or FTC and a third investigator-selected NRTI in fixed-dose combination (n: 209) Week 96 EXTENSION *Defined as >1 major or >2 minor LPV/r mutations LPV major mutations include the following mutations: V32I; I47V/A; L76V; V82A/F/T/S

55 Patients with HIV-1 RNA Viral load <50 copies/ml at weeks 48 and 96 (ITTe) 100% 90% 80% 70% Week 48 (p= 0.171, difference +4.6% [CI 95% : -2.2% to +11.8%]) 88.3% 90.3% 83.7% 84.4% <50 copies/ml (%) [1] 60% 50% 40% 30% 20% 10% Week 96 (p= 0.165, difference % [CI 95% : -2.3%; to 14.1 %]) 0% BSL W4 W8 W12 W24 W36 W48 W96 DT TT

56 PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE): Study design Phase IV, pilot, open-label, single arm exploratory trial ARV- naïve patients, 18 years HIV-1 RNA >5,000 copies/ml and <100,000 copies/ml CD4 count 200 cells/ml HB(s)Ag negative (n= 20) 1 st cohort (n= 10) DTG 50 mg QD 3TC 300 mg QD 2 nd cohort (n= 10) DTG 50 mg QD 3TC 300 mg QD Second cohort to be enrolled after confirming success of first cohort at week 8 Viral load was measured at baseline, days 2, 4, 7, 10, 14 and weeks 4, 8, 12 and 24 Primary endpoint Proportion of subjects with plasma HIV-1 RNA levels <50 copies/ml at week 48 using the FDA snapshot algorithm (missing, switch or discontinuation = failure) for the ITT-exposed population

57 Viral suppression at week 24 # SCR BSL DAY 2 DAY 4 DAY 7 DAY 10 W.2 W.3 W.4 W.6 W.8 W.12 W < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < Not done < 50 < 50 < 50 < 50 < 50 < Not done < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < < < 50 < 50 < 50 < < 50 < 50 < 50 Not done < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 From week 8 onwards all patients had pvl <50 copies/ml

58 NRTI-sparing regimens Regimen DRV/r + RAL (ACTG ) DRV/r + RAL (NEAT 2 ) DRV/r + MVC (MODERN 3 ) ATV/r + RAL (HARNESS 4 switch) LPV/r + RAL (PROGRESS 5 ) LPV/r + EFV (ACTG ) LPV/r + 3TC (GARDEL 7 ) LPV/r + 3TC or FTC (OLE 8 switch) ATV/r + 3TC (SALT 9 switch) Results Poor performance at high VL Less effective at high VL, low CD4 Less effective than standard ART Less effective than standard ART Small study; few pts with high VL Poorly tolerated but effective As effective as standard ART As effective as standard ART As effective as standard ART 1. Taiwo B, et al. AIDS. 2011;25: Raffi et al. CROI 2014, Abstract 84LB 3. Stellbrink H-J, et al. IAD Abstract MOAB Van Lunzen J et al. IAC Abstract A Reynes J, et al. AIDS Res Hum Retroviruses. 2013;29: Daar ES et al. Ann Intern Med 2011; 5;154: Cahn P, et al. Lancet Infect Dis 2014;14: Gatell J, et al. AIDS Abstract LBPE Perez-Molina, J.A., et al. IAC AbstractL BPE18

59 Mean change from baseline, % iprex: BMD Substudy Change from Baseline in Bone Mineral Density (BMD) Placebo TVD Spine (L1-L4) P=0.001 P=0.143 P= Week Mean, SE and P-values by linear mixed model 72 Total Hip Small but significant decreases in BMD at the spine, but not the hip, were observed in HIV-negative men randomized to TVD relative to placebo There were no differences in bone fractures between the groups (P=0.41) Placebo P<0.001 P=0.002 P= Week Placebo FTC/TDF TVD Mulligan K, et al. CROI 2011; Boston, MA. #94LB 60 6

60 iprex Renal Safety Renal safety assessment of 2499 HIV-negative subjects in iprex study A mild, non-progressive decrease in creatinine clearance (Cockcroft-Gault), that was reversible and readily managed with routine monitoring Did not vary by race, age, or HTN history Affected by NSAID use -3.4 ml/min (+NSAID) vs ml/min (no NSAID), P = 0.04 Mean Change in CrCL (ml/min) TVD Placebo P-value Wk At Stop Post-stop FTC/TDF Placebo Change in Creatinine Clearance from Baseline (ml/min)* * in 1,137 subjects Solomon M, et al. AIDS 2014;28(6): Week 61 6

61 PrEP Product Pipeline HIV PrEP Research Pipeline: Candidates for Systemic Delivery Medication Cabotegravir 1 Intramuscular Macaque study Cabotegravir 2,3,4 Intramuscular Phase 2a (ÉCLAIR) Maraviroc 5 Oral Phase 2 (HPTN069) TAF 6 Biodegradable implant Preclinical Outcome 21/24 (88%) macaques protected from intravenous SHIV challenge 98% (CAB) and 90% (PBO) had AEs grade % (CAB) vs 57% (PBO) had any injection site-related event More Grade 2-4 AEs in the CAB arm (80%) versus PBO arm (48%). Grade 2-4 AEs in CAB arm: 59% injection site pain, 7% pyrexia, 6% injection site pruritus, and 6% injection site swelling AEs similar among 4 arms 5 seroconversions: --1 in MVC+TDF arm (no drug at seroconversion) --4 in MVC arm (1 with higher than expected steady-state MVC level) Thin-film polycaprolactone delivery device releases drug over 3 mo Stable release rate moderated by size and film thickness 1. Andrews C, et al. CROI Boston, MA. # Markowitz M, et al. CROI Boston, MA. # Murray M, et al. CROI Boston, MA. # Meyers K, et al. CROI Boston, MA. # Gulick G, et al. CROI Boston, MA. # Schlesinger E, et al. CROI Boston, MA. #879 62

62 Percent protected CDC Proof of Concept Study: FTC/TAF for PrEP FTC/TAF PrEP Protects Macaques from Rectal SHIV Infection Treatment arm (n=6) Placebo arm (n=6) -24h SHIV +2h FTC/TAF -24h SHIV +2h PBO SHIV challenge repeated weekly for up to 19 weeks FTC/TAF prevents rectal SHIV infection in macaques to a degree similar to that previously found with FTC/TDF but with a substantially reduced TFV dose 1 FTC/TAF protected 100% of macaques (N=6) challenged with SHIV in a similar, preclinical trial FTC/TAF Placebo % 0% SHIV challenges (weeks, n) FTC/TAF should not be used for PrEP in humans until a planned clinical study is completed 1. Massud I, et al. CROI Boston, MA. # Heneine W, et al. CROI Denver, CO. #32LB 63

63 PrEP Product Pipeline HIV PrEP Research Pipeline: Candidates for Topical Delivery Medication Dapivirine 1 Vaginal ring Phase 3 (MTN020 Aspire) Dapivirine 2 Vaginal ring Phase 3 (Ring Study) TFV 3 Rectal gel Phase 2 (MTN017) TFV 4 Vaginal film Phase 1 Outcome 27% reduction in HIV acquisition risk Efficacy correlated with age (0% protection below age 21; 56% age 21-26) 31% reduction in HIV acquisition risk Good adherence results in further reduction in HIV acquisition risk Use of the gel in pre- and post-receptive anal sex (RAI) preferred over daily use and resulted in better adherence Adherence to RAI schedule was similar to adherence in oral FTC/TDF arm Well tolerated Decreased HIV p24 antigen expression in explants 1. Baeten J, et al. CROI Boston, MA. #109LB 2. Nel A, et al. CROI Boston, MA. #110LB 3. Cranston R, et al. CROI Boston, MA. #108LB 4. Bunge K, et al. CROI Boston, MA. #871 64

64 Can we live without nucleosides? NAÏVE THE JURY IS STILL OUT SWITCH PROBABLY WE CAN SALVAGE. YES WE CAN clinicaloptions.com/hi v 65

65 Can we live without nucleosides? NAÏVE THE JURY IS STILL OUT clinicaloptions.com/hi v 66

66 Can we live without nucleosides? NAÏVE THE JURY IS IN: NOT WITH PI,POSSIBLY WITH II clinicaloptions.com/hi v 67

67 N Can we live without nucleosides? NAÏVE THE JURY IS IN, NOT WITH PI,POSSIBLY WITH II SWITCH POSSIBLY FOR TOXICITY, NO ADVANTAGE FOR VF clinicaloptions.com/hi v 68

68 N Can we live without nucleosides? NAÏVE THE JURY IS IN, NOT WITH PI,POSSIBLY WITH II SWITCH POSSIBLY FOR TOXICITY, NO ADVANTAGE FOR VF SALVAGE. YES WE CAN clinicaloptions.com/hi v 69

69 N Can we live without nucleosides? NAÏVE THE JURY IS IN, NOT WITH PI,POSSIBLY WITH II SWITCH POSSIBLY FOR TOXICITY, NO ADVANTAGE FOR VF SALVAGE. YES WE CAN OFTEN BECAUSE WE HAVE TO clinicaloptions.com/hi v 70