Reduced Drug Regimens

Dr. Jose R Arribas @jrarribas

Financial disclosures JOSE R ARRIBAS Research Support: Speaker s Bureau: Viiv, Janssen, Abbvie, BMS, Gilead, MSD Board Member/Advisory Panel: Merck, Gilead Stock/Shareholder: None Consultant: None Employee: None Other: None 2

The thin harvest of reduced drug antiretroviral regimens in naïve 3

The thin harvest of reduced drug antiretroviral regimens in naïve 2016 Preferred ABC/3TC-DTG TDF/FTC-DTG TDF/FTC-RAL TAF/FTC/EVG/c 2016 Preferred ABC/3TC-DTG TDF (TAF)/FTC-DTG TDF (TAF)/FTC-RAL TDF (TAF)/FTC/EVG/c TDF (TAF)/FTC-DRV/r 2016 Preferred ABC/3TC-DTG TDF (TAF)/FTC-DTG TDF (TAF)/FTC-RAL TDF (TAF)/FTC/EVG/c TDF (TAF)/FTC-DRV/r(c) TDF (TAF)FTC-RPV

The thin harvest of reduced drug antiretroviral regimens in naïve 2016 Preferred ABC/3TC-DTG TDF/FTC-DTG TDF/FTC-RAL TAF/FTC/EVG/c 2016 Preferred ABC/3TC-DTG TDF (TAF)/FTC-DTG TDF (TAF)/FTC-RAL TDF (TAF)/FTC/EVG/c TDF (TAF)/FTC-DRV/r 2016 Preferred ABC/3TC-DTG TDF (TAF)/FTC-DTG TDF (TAF)/FTC-RAL TDF (TAF)/FTC/EVG/c TDF (TAF)/FTC-DRV/r(c) TDF (TAF)FTC-RPV Alternative Alternative Alternative DRV/r + RAL DRV/r + RAL <3 LPV/r + RAL <3 <3 LPV/r + 3TC LPV/r + 3TC DRV/r(c) + RAL LPV/r + 3TC

The thin harvest of reduced drug antiretroviral regimens in naïve 2009 2011 2013 2015 1999 2008 2010 2012 2014 2016 Lopinavir/r (MONARK) 6

MONARK Trial: point estimate of the difference 8% 8% Source: Delfraissy et al. AIDS 2008; 22:385 393 7

Reduced drug antiretroviral regimens + PI + NRTI + NNRTI PI/r + CCR5 + INI 8

The thin harvest of reduced drug antiretroviral regimens in naïve Atazanavir/r + Maraviroc (A4001078) Darunavir/r + Raltegravir (ACTG 5262) Lopinavir/r + Raltegravir (PROGRESS) 2009 2011 2013 2015 1999 2008 2010 2012 2014 2016 Indinavir + Efavirenz (006) Lopinavir/r + Efavirenz (ACTG 5142) Lopinavir/r (MONARK) Atazanavir/r + Vicriviroc (P04875) Atazanavir/r + Raltegravir (SPARTAN) Darunavir/r + Raltegravir (NEAT 001) Lopinavir/r + Lamivudine (GARDEL) Darunavir/r + Maraviroc (MODERN) Non nucleoside CCR5 inhibitor Integrase inhibitor Nucleoside 9

The thin harvest of reduced drug antiretroviral regimens in naïve 2009 2011 2013 2015 1999 2008 2010 2012 2014 2016 Darunavir/r + Maraviroc (MODERN) 10

Proportion of subjects with HIV-1 RNA <50 copies/ml MODERN Study HIV-1 RNA <50 copies/ml Over Time 100% MVC+DRV/r TDF/FTC+DRV/r 90% TDF/FTC 86.8% 348/401 subjects 80% 70% 60% 50% 40% 30% 20% 10% 0% MVC 77.3% 306/396 subjects Adjusted treatment difference (95% CI): -9.5% (-14.8%, -4.2%) BL 4 8 12 16 20 24 36 48 Week Mean CD4+ cell count changes at Week 48 (mean ± SD, cells/mm 3 ) MVC + DRV/r 195.3 ± 175.7 TDF/FTC + DRV/r 193.9 ± 175.7 Source: Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101 11

Proportion of patients with HIV-1 RNA <50 copies/ml (%) Treatment Response at Week 48 by Key Subgroups 100 MVC + DRV/r TDF/FTC + DRV/r 90 80 80,3 88,7 79,5 88,9 88,2 76,1 79,5 84,7 85,7 81,9 70 65,4 65,8 60 50 40 30 20 10 0 <100,000 copies/ml 100,000 copies/ml <200 cells/mm3 200-350 cells/mm3 >350-500 cells/mm3 >500 cells/mm3 No. of patients Total 253 315 282 318 53 81 66 83 25 38 40 45 121 159 142 161 101 127 100 118 59 72 66 77 Baseline HIV-1 RNA Baseline CD4+ Cell Count Source: Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101 12

The thin harvest of reduced drug antiretroviral regimens in naïve 2009 2011 2013 2015 1999 2008 2010 2012 2014 2016 Darunavir/r + Raltegravir (NEAT 001) 13

Primary endpoint at W96 by baseline characteristics Overall analysis: RAL + DRV/r non inferior to TDF/FTC + DRV/r RAL + DRV/r TDF/FTC + DRV/r Overall n = 805-1.1 8.6 17.4 % 13.7 % Baseline HIV-1 RNA < 100,000 c/ml n = 530-3.9 3.5 7 % 7 % > 100,000 c/ml n = 275-0.05 19.3 36 % 27 % p = 0.09* Baseline CD4+ < 200/mm 3 n = 123 4.7 30.8 39.0 % 21.3 % > 200/mm 3 n = 682-3.4 6.3 13.6 % 12.2 % p = 0.02* 9-10 0 10 20 30 Difference in estimated proportion (95% CI) RAL TDF/FTC; adjusted Source: Raffi F, et al. Lancet 2014; 384:1942 1951. 14

NEAT 001: Resistance No RAM at virological failure in the standard tenofovir/ emtricitabine plus darunavir/ritonavir regimen Source: Lambert-Niclot S, et al. Journal of Antimicrobial Chemotherapy 2016; 71:1056 1062. 15

The thin harvest of reduced drug antiretroviral regimens in naïve 2009 2011 2013 2015 1999 2008 2010 2012 2014 2016 Lopinavir/r + Lamivudine (GARDEL) 16

Patients with HIV-1 RNA Gardel Study: Results 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 Source: Cahn P et al. 15th European AIDS Conference. Barcelona, October 21-24, 2015. Abstract PS10/4. 17

Patients With HIV-1 RNA Gardel Study: Results High Viral Lose Viral load <50 copies/ml at weeks 48 and 96 (ITTe), baseline VL > 100,000 copies/ml < 50 copies/ml (%) [1] 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% W48 (p=0.145, difference +9.3% [CI 95% : -2.8% to +21.5%]) 87.2% 77.9% 90.7% 80.7% BSL W4 W8 W12 W24 W36 W48 W96 DT TT Source: Cahn P et al. 15th European AIDS Conference. Barcelona, October 21-24, 2015. Abstract PS10/4. W96 (p=0.163, difference % [CI 95% : -3.8% ; 23.7 %]) 18

Gardel Study: Resistance Protocol-Defined Virologic Failure and Emergent Resistance Mutations Number of patients, n (%) DT (n: 165) TT (n: 141) Confirmed virologic failures * 12 (7.3 % ) 9 (6.4 % ) HIV-1 RNA at failure (copies/ml) (median-iqr) 367 (110-3,185) 351 (88-23,491) Primary PI RAMs 0 0 NRTI RAMs (M184V) 4 3 * Emergent resistance mutations, in the 15 samples successfully amplified: DT: 4 out of 8 (M184V) TT: 3 out of 7 [M184V(2)/M184V/T215S(1)] Source: Cahn P et al. 15th European AIDS Conference. Barcelona, October 21-24, 2015. Abstract PS10/4. 19

Why 3TC closes the gap and not MVC or RAL? 20

Cambios basales en el ARN del VIH (log 10 ) 50mg QD 400mg BID 50mg QD + RTV 900mg BID 100mg BID 400mg BID + RTV 100mg BID 300mg BID 300mg BID INITIAL VIRAL LOAD DECREASES WITH DIFFERENT ANTIRETROVIRALS 0-0.5-1 -1.5-1.7-2 -2.03-2.5-2.46-3 INHIBIDORES DE LA INTEGRASA -1.99-1.96-1.85-1.42 OTROS ANTIRRETROVIRALES -1.19-0.52 1. Lalezari J. 5 th IAS 2009, Cape Town, abstract TUAB105. 2. DeJesus E. J Acquir Immune Defic Syndr 2006 ; 43:1-5. 3. Markowitz et al. JAIDS Volume 43(5) 15 December 2006 pp 509-515. 4. Sankatsing et al. AIDS 2003, 17:2623 2627. 5. Kilby JM. AIDS Res Hum Retroviruses 2002; 18:685-694. 6. Murphy RL. AIDS 2001;15:F1-F9. 7. Fätkenheuer G et al. Nat Med 2005 Nov; 11:1170-1172. 8. Eron JJ, N Engl J Med 1995, 333:1662-1669. Source: Lalezari, et. al. IAS 2009 5th Conference on HIV Pathogenesis, Treatment and Prevention 19-22 July 2009, Cape Town South Africa Abstract TUAB105 21

PENETRANCE IN TISSUE COMPARTIMENTS Source: Fletcher et al. Proc Natl Acad Sci USA 2014; 111:2307 2312. 22

PES: TDF/FTC-RAL 23

Antiretroviral drug half-lifes 24

Reduced drug regimens + NRTI INI 25

PADDLE: DTG + 3TC (Naïve) # SCR BSL DAY 4 DAY 7 W.2 W.3 W.4 W.6 W.8 W.12 W.24 W.36 W.48 1 5.584 10.909 383 101 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 2 8.887 10.233 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 3 67.335 151.569 1.565 1.178 97 53 < 50 < 50 < 50 < 50 < 50 < 50 < 50 4 99.291 148.370 3.303 432 178 55 < 50 < 50 < 50 < 50 < 50 < 50 < 50 5 34.362 20.544 1.292 570 107 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 6 16.024 14.499 1.634 162 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 7 37.604 18.597 819 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 8 25.071 24.368 1.377 Not done 105 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 9 14.707 10.832 516 202 < 50 < 50 < 50 < 50 < 50 < 50 < 50 SAE 10 10.679 7.978 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 11 50.089 273.676 68.129 3.880 784 290 288 147 < 50 < 50 < 50 < 50 < 50 12 13.508 64.103 3.296 135 351 84 67 < 50 < 50 < 50 < 50 < 50 < 50 13 28.093 33.829 26.343 539 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 14 15.348 15.151 791 198 < 50 61 64 < 50 < 50 < 50 < 50 < 50 < 50 15 23.185 23.500 4.217 192 < 50 < 50 < 50 Not done < 50 < 50 < 50 < 50 < 50 16 11.377 3.910 97 143 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 17 39.100 25.828 1.970 460 52 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 18 60.771 73.069 2.174 692 156 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 19 82.803 106.320 2.902 897 168 76 < 50 < 50 < 50 < 50 < 50 PDVF 20 5.190 7.368 147 56 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 Source: Cahn P, et al. AIDS 2016; Durban, South Africa; July 18-22, 2016; Abst. FARB0104LB. 26

GEMINI Studies 27

Reduced drug regimens regimens in suppressed Darunavir/r (PROTEA) various bpi (PIVOT) 2015 2005 2008 2010 2014 Lopinavir/r (OK Pilot) Lopinavir/r (OK 04) Darunavir/r (MONET) Atazanavir/r (MODAT) 28

Metaanálisis de estudios de monoterapia Source: Arribas JR et al. HIV Med Published Online First: 28 December 2015. doi:10.1111/hiv.12348 29

HIV-1 RNA <50 copies/ml at Week 48, FDA snapshot, switch=failure. PROTEA TRIAL HIV RNA <50 by Week 48 (%) 100 90 80 70 60 50 40 30 20 10 0 HIV RNA<50 Total Intent to Treat analysis (ITT) -8.7% (-1.8%, -15.5%) 86.1% 94.9% 89.4% 95.9% DRV/r mono DRV/r + 2NRTI DRV/r mono DRV/r + 2NRTI 118 137 129 136 Per Protocol analysis (PP) 110 123 118 123 Source: Antinori A,. AIDS 2015; 29:1811 1820 30

Reduced drug regimens regimens in suppressed Darunavir/r (PROTEA) various bpi (PIVOT) 2015 2005 2008 2010 2014 2016 Lopinavir/r (OK Pilot) Lopinavir/r (OK 04) Darunavir/r (MONET) Atazanavir/r (MODAT) various bpi + Maraviroc (MARCH) Atazanavir/r + RAL (HARNESS) Non nucleoside CCR5 inhibitor Integrase inhibitor Nucleoside 31

Reduced drug regimens regimens in suppressed 2015 2005 2008 2010 2014 2016 Atazanavir/r + RAL (HARNESS) 32

HARNESS Study Source: 20th International AIDS Conference July 20-25, 2014. LBPE19 33

Reduced drug regimens regimens in suppressed 2015 2005 2008 2010 2014 2016 various bpi + Maraviroc (MARCH) 34

MARCH: primary endpoint at week 48 Arm Below threshold (%) Difference (%) Intention to treat <200 cp/ml* Control 97.6 Reference 95% CI MVC+2N(t)RTI 93.6-4.0 (-9.0, 2.2) MVC+PI/r 84.1-13.5 (-19.8, -5.8) Noncompletion=failure <200 cp/ml* Control 96.3 Reference MVC+2N(t)RTI 88.5-7.9 (-14.1, -0.4) MVC+PI/r 80.3-16.1 (-23.1, -7.6) Per protocol <200 cp/ml* Control 98.8 Reference *results from <50 cp/ml were consistent MVC+2N(t)RTI 98.6-0.2 (-3.8, 4.4) MVC+PI/r 90.0-8.8 (-14.2, -2.1) Source: Pett S, et al; 15th EACS, Barcelona, Spain, October 21-24, 2015; Abst. BPD1/5 35

Reduced drug regimens regimens in suppressed Atazanvir/r + 3TC (SALT) Lopinavir/r + 3TC (OLE) Darunavir/r (PROTEA) various bpi (PIVOT) Darunavir/r + 3TC (DUAL) 2015 2005 2008 2010 2014 2016 Lopinavir/r (OK Pilot) Lopinavir/r (OK 04) Darunavir/r (MONET) Atazanavir/r (MODAT) various bpi + Maraviroc (MARCH) Atazanavir/r + RAL (HARNESS) Non nucleoside CCR5 inhibitor Integrase inhibitor Nucleoside 36

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Reduced drug regimens regimens in suppressed Lopinavir/r + 3TC (OLE) Darunavir/r + 3TC (DUAL) 2015 2005 2008 2010 2014 2016 38

DUAL Study Design VL < 50 c/ml > 6 months No resistance to DRV/r o 3TC On treatment with DRV/r + ABC/3TC or TDF/FTC 2 months HBsAg negative Randomized 1:1. Stratified by baseline nucleos(t)ides DUAL TRIPLE DRV/r QD + 3TC QD DRV/r QD + ABC/3TC or TDF/FTC 4 12 24 36 48 Weeks Primary Analysis Source: Arribas J, et al. HIV Glasgow; 23-26 October 2016; Glasgow, UK; Abst. O331. 39

Proportion ofpatients with HIV viral load <50 copies/ml (%) Difference (%) IC 95% DUAL Study: Sensitivity analysis 12 0 3.4-3.8 5.7-2.2 3.9-3.4 2.4-1.7-5.8-12 DUAL TRIPLE 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% -11-10.2-10.7 97% 98% 93% 93% 89% 87% 89% 89% ITT-e (snapshot) ITT (snapshot) Per-Protocol (snapshot) Observed data Observed data: excluding non-virological reasons for failure. Source: Arribas J, et al. HIV Glasgow; 23-26 October 2016; Glasgow, UK; Abst. O331. 40

DUAL Study: Continuous viral load suppression HIV- viral load less than 50 copies/ml in all the visits (%) Blips 100% 80% 60% 40% 20% 0% 82.5% 82.9% DUAL TRIPLE DUAL TRIPLE 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 13.2% 8.9% 4.5% 2.6% 0.9% 0.0% Single Double Triple p =0.94 p=0.31 p=0.46 p=0.31 Including all patients who completed 48 weeks of treatment and had viral loads measurements in all visits. Only patients who had HIV-RNA < 50 copies at week 48. Blip defined as a transitory viral load 50 copies/ml Source: Arribas J, et al. HIV Glasgow; 23-26 October 2016; Glasgow, UK; Abst. O331. 41

DUAL Study: Resistance testing (attempted in all rebounds with viral loads > 400 HIV-RNA copies/ml) GROUP Week HIV-RNA 50 c/ml week 48 (SNAPSHOT) 1 st viral load 2 nd viral load Genotype Mutations DUAL Baseline Yes 80 800 Yes None DUAL 24 Yes 988 259 Failed DUAL 32 No 6,805 165 Yes None TRIPLE 24 No 427 <20 Failed TRIPLE 24 No 447,557 5,621 Yes V10I, W71T, D76W Source: Arribas J, et al. HIV Glasgow; 23-26 October 2016; Glasgow, UK; Abst. O331. 42

Reduced drug regimens regimens in suppressed Less than three drugs antiretroviral regimens in suppressed Atazanvir/r + 3TC (SALT) Lopinavir/r + 3TC (OLE) Darunavir/r (PROTEA) various bpi (PIVOT) Darunavir/r + 3TC (DUAL) 2015 2005 2008 2010 2014 2016 Non nucleoside CCR5 inhibitor Lopinavir/r (OK Pilot) Lopinavir/r (OK 04) Darunavir/r (MONET) Atazanavir/r (MODAT) Atazanavir/r + RAL (HARNESS) Cabotegravir + Rilpivirine (oral, LATTE) various bpi + Maraviroc (MARCH) Cabotegravir + Rilpivirine (IM, LATTE-2) Integrase inhibitor Nucleoside Integrase inhibitor and Non nucleoside 43

Reduced drug regimens regimens in suppressed Less than three drugs antiretroviral regimens in suppressed Darunavir/r + 3TC (DUAL) 2015 2005 2008 2010 2014 2016 Cabotegravir + Rilpivirine (oral, LATTE) 44

LATTE Study Design Phase IIb, randomized, multicenter, partially blind, dose-ranging study 744 + NRTI subjects with a W20 HIV-1 RNA <50 c/ml simplified to 744 + RPV at W24 Oral Induction Phase Oral Maintenance Phase HIV ART-naive HIV-1 RNA 1000 c/ml CD4 200 cells/mm 3 1:1:1:1 Randomization Stratified by VL and NRTI 744 10 mg + 2 NRTIs* 744 30 mg + 2 NRTIs 744 60 mg + 2 NRTIs 744 10 mg + RPV 25 mg 744 30 mg + RPV 25 mg 744 60 mg + RPV 25 mg EFV 600 mg + 2 NRTIs D1 Week 16 20 24 48 72 96 *ABC/3TC or TDF/FTC 45

Proportion, % LATTE Study Design. Primary Endpoint Virologic Success: HIV-1 RNA <50 c/ml by FDA Snapshot (ITT-E) 100 744 overall response W24 744 overall response W48 87% 82% Induction Phase Maintenance Phase 80 60 40 20 0 BL EFV response W24 74% Week Median (IQR) change from baseline CD4+ cell count (cells/mm 3 ) Week 48 744 overall +219 (141,343) EFV +227 (134,369) EFV response W48 71% 2 4 8 12 16 24 26 28 32 36 40 48 744 10 mg (N=60) 744 30 mg (N=60) 744 60 mg (N=61) EFV 600 mg (N=62) Source: Margolis et al. CROI 2014; Boston, MA. Abstract 91LB. 46

Reduced drug regimens regimens in suppressed Darunavir/r + 3TC (DUAL) 2015 2005 2008 2010 2014 2016 Cabotegravir + Rilpivirine (IM, LATTE-2) 47

Estudio LATTE-2 48

SWORD Studies 49

Reduced drug regimens regimens in suppressed Darunavir/r + 3TC (DUAL) 2015 2005 2008 2010 2014 2016 Cabotegravir + Rilpivirine (IM, LATTE-2) 50

Reduced drug regimens regimens in suppressed Darunavir/r + 3TC (DUAL) 2015 2005 2008 2010 2014 2016 Cabotegravir + Rilpivirine (IM, LATTE-2) DTG (DOLUMONO 51

RCT of Continued ART vs DTG Mono Therapy in Selected Suppressed Subjects Patients, % Virologic Outcome DTG Monotherapy n=50 c-art n=53 100 100 98, 100, 92, 75, 50, 25, 0, Success <200 Success <50 Discontinued 1, 0 Source: Wijting I, et al. HIV Glasgow; 23-26 October 2016; Glasgow, UK; Abst. O333. 52

Reduced drug regimens Numerous attempts to treat ART naïve and suppressed patients with reduced drug regimens have failed bpi monotherapy bpi + ISTI bpi + CCR5I bpi + 3TC or DTG + 3TC still have potential in naïve bpi + 3TC: 4 trials have convincingly stablished efficacy in suppressed CTG+RPV (oral or long acting) promising in suppressed 53

Acknowledgments HIV Unit at La Paz Hospital 54