NUEVOS ENFOQUES TERAPEUTICOS

Transcription

1 NUEVOS ENFOQUES TERAPEUTICOS -11ºC Daniel Podzamczer Unidad VIH. S Enf. Infecciosas Hospital Universitari de Bellvitge L Hospitalet. Barcelona

2 AGENDA ART simplification QD regimen: RAL Bitherapy: DRVr/RAL Monotherapy as second line: LPV/r Intensification strategies Early infection: 3 vs 5 drugs Chronic infection: MVC RAL Long term follow up of previously published studies STARTMRK MONOI TRIO ART as pre-exposure prophylaxis

3 CROI LB QDMRK, A Phase III Study of the Safety & Efficacy of Once Daily (QD) Versus Twice Daily (BID) Raltegravir (RAL) in Combination Therapy for Treatment-Naïve HIV- Infected Patients (Pts) J. Eron 1, J. Rockstroh 2, J. Reynes 3, J. Andrade 4, J. Madruga 5, J. Zhao 6, P. Sklar 6, B-Y. Nguyen 6 for the QDMRK Study Team 1 Univ. of North Carolina, Chapel Hill, NC, USA; 2 Univ. of Bonn, Bonn- Venusberg, Germany; 3 Montpellier Univ. Hospital, Montpellier, France; 4 Universidad de Guadalajara, Mexico; 5 Centro de Referência DST/AIDS, São Paulo, Brazil and 6 Merck Research Laboratories, North Wales, PA, USA 3

4 QDMRK (P071) Study Design Multicenter, double-blind, randomized, active-controlled study Non-inferiority design (10% margin) Primary endpoint Week 48 Secondary endpoint Week 96 HIV-1-infected Treatment naive HIV-1 RNA >5000 copies/ml No CD4 cell cut-off No documented resistance to tenofovir or emtricitabine 1:1 Raltegravir 800 mg QD + TDF/FTC FDC n=382 Raltegravir 400 mg BID + TDF/FTC FDC n= % with vrna >100,000 copies/ml ml; ; mean CD /uL; 279/uL; 23-26% 26% with CD4 200 cells/µl

5 QDMRK Baseline Characteristics RAL QD* RAL BID* # Patients Treated N = 382 N = 388 Age (median, years) % Male % Non-White vrna copies/ml (geometric mean) 67,968 70,942 % with vrna >10 5 copies/ml Mean CD4 count (cells/µl) l) % with CD4 200 cells/µl % Hepatitis B or C 7 6 % Non-Clade B *In combination with TDF/FTC FDC

6 QDMRK % of Patients with HIV RNA < 50 copies/ml (NC=F ) 100 BID 88.9% Percent of Patients with HIV RNA <50 Copies/mL QD 83.2% Δ (QD-BID) [95% CI] = -5.7 [-10.7,[ -0.83] Number of Contributing Patients Study Week RAL 800 mg QD RAL 400 mg BID *All patients received TDF/FTC FDC Non-completer equals failure (NC=F) approach treats all discontinuations as failures

7 CROI LB QDMRK HIV RNA < 50 copies/ml at Week 48 by Subgroup (NC=F) Response Difference RAL QD n/n % RAL BID n/n % % (95% CI) Baseline HIV RNA (copies/ml) > 100,000 copies/ml 113/ ,000 copies/ml 205/230 Baseline CD4 (cells/mm 3 ) / / (-19.0,( -0.8) (-8.3,( 2.7) 200 cells/mm 3 63/ / (-22.3,( 2.2) > 200 cells/mm 3 254/ / (-9.8,( 0.4) Copyright 2011 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All rights Reserved 7

8 CROI LB QDMRK Time to Loss of Virologic Response (TLOVR) TLOVR (OF) Patients With BL vrna >100,000 cp/ml 100 TLOVR (OF) Patients With BL vrna <=100,000 cp/ml 100 Percent of Event Free HR (0.276, 0.867) P-value Percent of Event Free HR (0.250,1.308) p-value RAL 800 mg QD RAL 400 mg BID Week Number of Patients at Risk RAL 800 mg QD RAL 400 mg BID Number of Patients at Risk Week Copyright 2011 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All rights Reserved 8

9 CROI LB QDMRK - 48 Week Summary of Virologic Failures & Resistance Data Raltegravir QD Raltegravir BID Number of VF by Baseline HIV RNA Virologic Failures VF >400 c/ml, (data available) 53/382 (13.9%) 35/388 (9.0%) 30 (27 with IN data) 16 (12 with IN data) BL VL (cp/ml ml) Raltegravir QD 100, Raltegravir BID 8 No Evidence of Resistance 7 7 > 100, Integrase Resistance and FTC Resistance FTC Resistance Alone Definition Of Virologic Failure 1. HIV RNA >50 copies/ml at Week 24 (confirmed at least 1 week apart), OR 2. virologic relapse after initial response: HIV RNA>50 copies/ml (on 2 consecutive measurements at least 1 week apart) after initial response with HIV RNA <50 copies/ml Most Pts failed with 2 or more mutations known to be associated with RAL resistance. Signature mutations included N155H (4 pts in QD), Y143C/R (3 pts in QD, 1 pt in BID) NOTE: No Patient in Either Arm Failed with Evidence of TDF Resistance Copyright 2011 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All rights Reserved 9

10 QDMRK Histograms for GM C trough and % with HIV RNA <50 copies/ml (Observed Failure) GM C12hr (nm) GM C24hr (nm) Range Median Range Median Overall Responses: 400 mg BID 92% 800 mg QD 87% In 800 mg QD dataset, there is a drop-off in efficacy for patients in lowest C trough quartile

11 QDMRK message QD RAL was inferior in virologic efficacy compared to BID RAL-based regimens in treatment naïve patients

12 #551 Results from a Single Arm Study of Darunavir/Ritonavir plus Raltegravir in treatment-naïve HIV-1 infected patients (ACTG A5262) Taiwo B, et al.

13 Methods Design: Multicenter single-arm open, 52 week pilot study. Intervention: RAL 400 mg BID + DRV/r 800/100 mg QD Patients ARV-naïve: VL 5000 c/ml; 1 mut DRV; no mut may II End-point: VF week 24 (wk 12 VL 1000c/ml or rebound; wk 24 VL 50 c/ml)

14 RESULTS

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18 Message * DRV/r + RAL associated with VF and RAL resistance in pts with >100,000 c/ml

19 Second line Lopinavir/RitonavirMonotherapywas Inferior to Tenofovir/Lamivudine/Lopinavir/Ritonavir in Patients who Failed NNRTI-Regimen: HIV STAR Study TorsakBunupuradah 1, PloenchanChetchotisakd 2, JintanatAnanworanich 1,3,4, WarangkanaMunsakul 5, SupanneeJirajariyavet 6, PachareeKantipong 7, WisitPrasithsirikul 8, SomnuekSungkanuparph 9, ChureeratanaBowonwatanuwong 10, ViratKlinbuayaem 11, Bernard Hirschel 12, SorakijBhakeecheep 13, KiatRuxrungtham 1,4 and HIV STAR study team 1 HIV-NAT, the Thai Red Cross AIDS Research Centre, Bangkok, Thailand;2 KhonKaenUniversity, KhonKaen, Thailand; 3 SEARCH, the Thai Red Cross AIDS Research Centre Bangkok, Thailand; 4 Facultyof Medicine, ChulalongkornUniversity, Bangkok, Thailand; 5 Faculty of Medicine Vajira Hospital, University of Bangkok Metropolitan Administration, Thailand; 6 Taksin Hospital, Bangkok, Thailand; 7 Chiangrai PrachanukrohHospital, Chiangrai, Thailand; 8 BamrasnaraduraInstitute, Nonthaburi, Thailand; 9 RamathibodiHospital, Bangkok, Thailand; 10 ChonburiHospital, Chonburi, Thailand; 11 SanpatongHospital, Chiang Mai, Thailand; 12 Geneva University, Geneva, Armadillo Medical Group Switzerland; 13 The National Health Security Office (NHSO), Thailand

20 Baseline characteristics Mono-LPV/r-arm N=98 TDF/3TC/LPV/r-arm N=97 Total N=195 Age (years) 36.7 ( ) 37.6 ( ) 37.1 ( ) % male 67% 48% 58% Weight (kg) 58.2 ( ) 57.0 ( ) 57.8 ( ) Height (cm) 165 ( ) 161.5( ) 165 ( ) % CDC clinical classification A:B:C 25:20:55 22 :24:54 23:22:55 % Nevirapine:Efavirenz 88:12 % 84:16 % 86:14 % Duration of NNRTI-based HAART before enrollment(years) 3.0 ( ) 3.2( ) 3.0( ) Baseline CD4 count (cells/mm3) 184 ( ) 198 ( ) 188 ( ) % of patients with baseline CD4 count <100 cells/mm % 24.7% 22.6% Baseline HIV-RNA (log 10 copies/ml) 4.0 ( ) 4.2 ( ) 4.1 ( ) Armadillo Medical Group

21 Baseline characteristics Baseline Resistance Mutations Mono-LPV/r-arm N=98 TDF/3TC/LPV/r-arm N=97 Total N=195 % patients with M184V K65R 3 TAMS 3 TAMS or Q151M 4 TAMS multi NRTI mutation* 83.7% 6.1% 31.6% 35.7% 9.2% 13.3% 80.4% 7.2% 25.8% 30.9% 13.4% 21.6% 82.1% 6.7% 28.7% 33.3% 11.3% 17.5% Armadillo Medical Group

22 Proportion of patients with virological suppression at week 48 (fail = missing or addition of 2 NRTIsto monotherapyarm) % virological suppression (ITT) VL >400 copies/ml VL <400 copies/ml (p=0.053) VL <200 copies/ml (p=0.01) VL <50 copies/ml (p=0.01) 0 Mono-LPV/r-arm TDF/3TC/LPV/r-arm Note: intention to treat analysis (ITT); missing or adding TDF/3TC equals to failure VL; plasma HIV-RNA, LPV/r; lopinavir/ritonavir, TDF/3TC; tenofovir/lamivudine Armadillo Medical Group

23 Proportion of patients with virological suppression at week 48 (missing equals to failure) % virological suppression (ITT) VL >400 copies/ml VL <400 copies/ml (p=0.58) VL <200 copies/ml (p=0.10) VL <50 copies/ml (p=0.01) 0 Mono-LPV/r-arm TDF/3TC/LPV/r-arm Note: intention to treat analysis (ITT); missing equals to failure VL; plasma HIV-RNA, LPV/r; lopinavir/ritonavir, TDF/3TC; tenofovir/lamivudine Armadillo Medical Group

24 Resistance Genotyping resistance test were performed in 2 patients in mono-lpv/r-arm and 3 patients in TDF/3TC/LPV/r-arm. Major PI mutations (M46I, I50V) were detected in 1 patient in the mono-lpv/r-arm, whereas none was detected in TDF/3TC/LPV/r-treated subjects Armadillo Medical Group

25 Message * LPV/r monotherapy in failing pts associated with > VF than triple ART

26 #148LB A Randomized Open-label Trial of 5- Drug vs 3-Drug Standard PI-based cart Initiated during Acute and Early HIV-1Infection: 48-Week Results Markowitz M, et al

27 Design TDF/FTC + ATV/r or DRV/r 40 patients Acute infection No resistence 96 weeks Same + MVC 150 BID & RAL 400 BID Primary End Point: % patients with VL< 50 and 1 copy/ml at week 48

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32 Message The addition of MVC and RAL to ART in early HIV infection not associated with virologic or immunologic benefit (pending studies in GI lymphoid tissue and residual infectious virus in resting CD4)

33 #153LB The Imunomodulatory Effects of Maraviroc Intensification among ART-suppressed Patients with Incomplete CD4 Recovery Hunt P, et al

34 * * CV < 50 c/ml; CD4 < 350/uL; aumento de CD4 < 100 último año

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40 #51 Raltegravir Intensification of Patients on Long Term Suppressive Antiretroviral Therapy Does Not Increase 2 LTR HIV DNA Circles In Peripheral Blood Mononuclear Cells. Results from ACTG A5244 Gandhi R, Coombs R, Chan E, Bosch R, Zheng S, Margolis D, Read S, D Aquila R, Mellors J, Eron J on behalf on the AIDS Clinical Trials Group A5244 Team

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45 Raltegravir (RAL) Demonstrates Durable Virologic Suppression and Superior Immunologic Response with a Favorable Metabolic Profile Through 3 Years of Treatment (Tx): 156 Week (Wk) Results from STARTMRK J. K. Rockstroh, J. Lennox, E. DeJesus, M. Saag, A. Lazzarin, X. Xu, H. Teppler, B-Y. Nguyen, R. Leavitt, P. Sklar and the STARTMRK Study Team Copyright 2011 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All rights Reserved 45

46 Proportion (%) of Patients (95% CI) with HIV RNA <50 c/ml through 156 Weeks (NC = F) Percent of Patients with HIV RNA <50 Copies/mL Δ (RAL-EFV) [95% CI] = +7.3 [-0.2, +14.7] Non-Inferiority p-value < Number of Contributing Patients Weeks Raltegravir group Efavirenz group

47 Change from Baseline in CD4 Cell Count (Observed Failure Approach) Change from Baseline CD4 Cell Count (cells/mm 3 ) (RAL-EFV)[95%CI] = +37 [+4,+69] Number of Contributing Patients Weeks Raltegravir group Efavirenz group

48 Mean Change from Baseline in Metabolic Parameters at Week Raltegravir Efavirenz Mean Change (mg/dl) p<0.001 * p=0.137 * 0 T CHOL HDL-C LDL-C TG Glucose The change from baseline in the T CHOL:HDL-C ratio was for the RAL group and 0.04 for EFV group (p=0.061)

49 Mean Percent (%) Change (SE) in Trunk Fat over Time (Patients with DEXA at BL and Wk 156) Trunk Fat Mean Percent (SE) Change Weeks Number of Contributing Patients RAL group EFV group

50 Mean Percent (%) Change (SE) in Appendicular Fat Over Time (Patients with DEXA at BL and Wk 156) Appendicular Fat Mean Percent (SE) Change Weeks Number of Contributing Patients RAL group EFV group

51 #534 Long-term Efficacy of Darunavir/Ritonavir Monotherapy in Patients with HIV-1 viral supression in MONOI-ANRS 136 Study: Results at 96 weeks Valantin M-A, et al

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56 #533 Baseline HIV RNA Ultrasensitive Basal and Viral DNA Predict Rise in Plasma Viral Load in Patients of MONOI-ANRS 136 Trial (DRV/r Monotherapy vs 2 NRTI + DRV/r) Marcelin, A-G, et al

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58 Virologic Failure Mono Triple Patients with 1 VL > 50 c/ml 41% 29% Patients with 3 VL > 50 c/ml 19% 8% Patients with Virologic rebound Do-w % vs 1.8% (p=0.002) Do-w % vs 8% (P=0.005)

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60 Conclusiones DRVr monotherapy associated with increased risk of VR Factors associated with viral rebound: At 48w: single blip at D0 and/or not having baseline VL < 1 copy/ml At 96w: < time of prior ART (5.1 years vs 8.9) > HIV-1 DNA at D0 (4.2 vs 3.9 log 10 / 10 6 cell < adherence (48.5% patients vs 31.6%)

61 #549 Long-term Follow Up of Patients Receiving Raltegravir, Etravirine, and Darunavir/Ritonavir in the ANRS 139 TRIO Trial Fagard C, et al

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65 N Engl J Med 2010; 363:

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71 CROI 2010 Abstract # K-135 Copyright 2011 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All rights Reserved 71

72 Prep Iprex-small but significant decreases in BMD in those on TDF/FTC [94LB] Although statistically different, differences at hip and spine less than 1.0% over weeks Minor variant resistance not found consistent with low drug exposure amongst failures [97LB] Cost effectiveness models for South Africa suggest that Prep associated with cost of $1200-$4500 per year of life saved [37LB]

73 Moltes gràcies! Por un CROI en primavera!! Por un CROI en primavera!!!!

74 25 anys de assistència i tractament a pacients infectats pel VIH Htals Bellvitge, Clínic, Germans Trías 28 març: Palau Moxó. 21 hs 29 març: Saló d actes. HUB (13-15 hs)