Reduced Drug Regimens

Transcription

1 Dr. Jose R

2 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

3 The thin harvest of reduced drug antiretroviral regimens in naïve 3

4 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

5 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

6 The thin harvest of reduced drug antiretroviral regimens in naïve Lopinavir/r (MONARK) 6

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

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

9 The thin harvest of reduced drug antiretroviral regimens in naïve Atazanavir/r + Maraviroc (A ) Darunavir/r + Raltegravir (ACTG 5262) Lopinavir/r + Raltegravir (PROGRESS) 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

10 The thin harvest of reduced drug antiretroviral regimens in naïve Darunavir/r + Maraviroc (MODERN) 10

11 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 Week Mean CD4+ cell count changes at Week 48 (mean ± SD, cells/mm 3 ) MVC + DRV/r ± TDF/FTC + DRV/r ± Source: Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB

12 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 ,3 88,7 79,5 88,9 88,2 76,1 79,5 84,7 85,7 81, ,4 65, <100,000 copies/ml 100,000 copies/ml <200 cells/mm cells/mm3 > cells/mm3 >500 cells/mm3 No. of patients Total Baseline HIV-1 RNA Baseline CD4+ Cell Count Source: Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB

13 The thin harvest of reduced drug antiretroviral regimens in naïve Darunavir/r + Raltegravir (NEAT 001) 13

14 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 = % 13.7 % Baseline HIV-1 RNA < 100,000 c/ml n = % 7 % > 100,000 c/ml n = % 27 % p = 0.09* Baseline CD4+ < 200/mm 3 n = % 21.3 % > 200/mm 3 n = % 12.2 % p = 0.02* Difference in estimated proportion (95% CI) RAL TDF/FTC; adjusted Source: Raffi F, et al. Lancet 2014; 384:

15 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:

16 The thin harvest of reduced drug antiretroviral regimens in naïve Lopinavir/r + Lamivudine (GARDEL) 16

17 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, Abstract PS10/4. 17

18 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, Abstract PS10/4. W96 (p=0.163, difference % [CI 95% : -3.8% ; 23.7 %]) 18

19 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, Abstract PS10/4. 19

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

21 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 INHIBIDORES DE LA INTEGRASA OTROS ANTIRRETROVIRALES Lalezari J. 5 th IAS 2009, Cape Town, abstract TUAB DeJesus E. J Acquir Immune Defic Syndr 2006 ; 43: Markowitz et al. JAIDS Volume 43(5) 15 December 2006 pp Sankatsing et al. AIDS 2003, 17: Kilby JM. AIDS Res Hum Retroviruses 2002; 18: Murphy RL. AIDS 2001;15:F1-F9. 7. Fätkenheuer G et al. Nat Med 2005 Nov; 11: Eron JJ, N Engl J Med 1995, 333: Source: Lalezari, et. al. IAS th Conference on HIV Pathogenesis, Treatment and Prevention July 2009, Cape Town South Africa Abstract TUAB105 21

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

23 PES: TDF/FTC-RAL 23

24 Antiretroviral drug half-lifes 24

25 Reduced drug regimens + NRTI INI 25

26 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 < 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 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < Not done 105 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 SAE < 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 < 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 PDVF < 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

27 GEMINI Studies 27

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

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

30 HIV-1 RNA <50 copies/ml at Week 48, FDA snapshot, switch=failure. PROTEA TRIAL HIV RNA <50 by Week 48 (%) 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 Per Protocol analysis (PP) Source: Antinori A,. AIDS 2015; 29:

31 Reduced drug regimens regimens in suppressed Darunavir/r (PROTEA) various bpi (PIVOT) 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

32 Reduced drug regimens regimens in suppressed Atazanavir/r + RAL (HARNESS) 32

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

34 Reduced drug regimens regimens in suppressed various bpi + Maraviroc (MARCH) 34

35 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 (-9.0, 2.2) MVC+PI/r (-19.8, -5.8) Noncompletion=failure <200 cp/ml* Control 96.3 Reference MVC+2N(t)RTI (-14.1, -0.4) MVC+PI/r (-23.1, -7.6) Per protocol <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) Source: Pett S, et al; 15th EACS, Barcelona, Spain, October 21-24, 2015; Abst. BPD1/5 35

36 Reduced drug regimens regimens in suppressed Atazanvir/r + 3TC (SALT) Lopinavir/r + 3TC (OLE) Darunavir/r (PROTEA) various bpi (PIVOT) Darunavir/r + 3TC (DUAL) 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

37 37

38 Reduced drug regimens regimens in suppressed Lopinavir/r + 3TC (OLE) Darunavir/r + 3TC (DUAL)

39 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 Weeks Primary Analysis Source: Arribas J, et al. HIV Glasgow; October 2016; Glasgow, UK; Abst. O

40 Proportion ofpatients with HIV viral load <50 copies/ml (%) Difference (%) IC 95% DUAL Study: Sensitivity analysis DUAL TRIPLE 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% % 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; October 2016; Glasgow, UK; Abst. O

41 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; October 2016; Glasgow, UK; Abst. O

42 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 Yes None DUAL 24 Yes Failed DUAL 32 No 6, 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; October 2016; Glasgow, UK; Abst. O

43 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) 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

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

45 LATTE Study Design Phase IIb, randomized, multicenter, partially blind, dose-ranging study NRTI subjects with a W20 HIV-1 RNA <50 c/ml simplified to 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 mg + 2 NRTIs* mg + 2 NRTIs mg + 2 NRTIs mg + RPV 25 mg mg + RPV 25 mg mg + RPV 25 mg EFV 600 mg + 2 NRTIs D1 Week *ABC/3TC or TDF/FTC 45

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

47 Reduced drug regimens regimens in suppressed Darunavir/r + 3TC (DUAL) Cabotegravir + Rilpivirine (IM, LATTE-2) 47

48 Estudio LATTE-2 48

49 SWORD Studies 49

50 Reduced drug regimens regimens in suppressed Darunavir/r + 3TC (DUAL) Cabotegravir + Rilpivirine (IM, LATTE-2) 50

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

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

53 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

54 Acknowledgments HIV Unit at La Paz Hospital 54