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ICAAC ARTEMIS DeJesus FINAL 18_09_07 w NRTIs

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									Efficacy and Safety of Darunavir/ritonavir versus
   Lopinavir/ritonavir in ARV Treatment-Naïve
       HIV-1-Infected Patients at Week 48:
            ARTEMIS (TMC114-C211)
      DeJesus E, Ortiz R, Khanlou H, Voronin E,
     Van Lunzen J, Andrade-Villanueva J, Fourie J,
          De Meyer S, Haley M, Lefebvre E,
        Vanden Abeele C, Spinosa-Guzman S
         ARTEMIS: Phase III study design

                                DRV/r 800/100mg qd
689 ARV-naïve
patients             + TDF 300 mg and FTC 200 mg (N=343)
VL>5,000;
no CD4 entry     LPV/r 400/100mg bid or 800/200mg qd
                    + TDF 300 mg and FTC 200 mg (N=346)



                 LPV dosing                     LPV formulation
                 qd =       15%                 Capsule only =                  15%
                 bid =      77%                 Tablet only =                   2%
                 bid/qd =     7%                Capsule/tablet switch = 83%
                 Dosing was based on regulatory approval; switch was made
                 according to local regulatory approval and drug availability
        ARTEMIS: Study objectives
• Primary end point
  – Proportion of patients with an HIV RNA <50 copies/ml
    at Week 48
• Primary objective
  – demonstrate non-inferiority of DRV/r qd vs LPV/r
    based on that primary end point
• Secondary objectives
  – evaluate long-term safety, tolerability and durability
    of virologic responses
  – compare immunologic responses
  – conduct pharmacokinetic evaluations
     ARTEMIS: Baseline characteristics
                                        DRV/r qd        LPV/r qd or bid
                                        (N=343)            (N=346)

Baseline demographics
  Female, N (%)                          104 (30)          105 (30)
  Mean (±SD) age (yrs)                    36 (9)            35 (9)
  Caucasian/Black/Hispanic, %           40/23/23           44/21/22

Baseline disease characteristics
  Median HIV-1 RNA (cpm)                  70,800            62,100
  (range)                             (835–5,580,000)   (667–4,580,000)
  Median CD4 (cells/mm3 [range])       228 (4–750)        218 (2–714)
  HBV/HCV co-infected, n (%)              43 (13)           48 (14)


Stratification factors at screening
  CD4 count <200 cells/mm3                 40%               41%
  Plasma HIV-1 RNA ≥100,000 cpm            36%               36%
           ARTEMIS: Patient disposition
                                                    DRV/r qd         LPV/r qd or bid
Incidence (%)                                       (N=343)             (N=346)
Discontinuation                                     41 (12%)              56 (16%)
  AE*                                               12 (3%)               24 (7%)
  Lost to follow-up                                 14 (4%)               10 (3%)
  Withdrawal of consent                              4 (1%)                 5 (1%)
  Virologic failure                                  2 (<1%)                6 (2%)
  Pregnancy                                          5 (1%)                 3 (<1%)
  Non-compliance                                     2 (<1%)                5 (1%)
  Other                                              2 (<1%)                3 (<1%)

*Four deaths (1 in DRV/r group; 3 in LPV/r group)


               Table includes all data up to the point when the last patient reached week 48
                                         Mean exposure was 56 weeks (range 0–83 weeks)
                                           ARTEMIS: Viral load <50 copies/mL
                                               to Week 48 (ITT-TLOVR)
Patients with VL <50 copies/mL (% [±SE])



                                           100                                                           DRV/r qd (N=343)

                                            90                                                           LPV/r qd or bid (N=346)
                                                                                                                      84%
                                            80
                                                                                                                      78%
                                            70
                                            60
                                            50
                                            40
                                                                Estimated difference in response vs LPV/r for non-inferiority:
                                            30
                                                                PP = 5.6% (95% CI –0.1;11.3) p<0.001
                                            20                  Estimated difference in response vs LPV/r for superiority:
                                            10                  ITT = 5.5% (95% CI –0.3;11.2) p=0.062

                                            0
                                                 2 4   8   12        16     24                 36                48
                                                                     Time (weeks)
                                     ARTEMIS: Confirmed response by baseline
                                        VL or CD4 at Week 48 (ITT-TLOVR)
                                                                              DRV/r qd   LPV/r qd or bid
                   100                                                                                             100
                                                                    †p<0.05   vs LPV/r
Patients with VL <50 copies/mL (%)




                                                                                         Patients with VL <50 copies/mL (%)
                                             86           85                                                                                                 87
                                                                                                                                                                  84
                                          n=194 n=191      n=28      79†                                                                         80
                                 80                                                                                           80    77
                                                                               67                                                                      71
                                                                                                                                            67

                                     60                                                                                       60


                                     40                                                                                       40


                                     20                                                                                       20

                                                                                                                                                                  0

                                      0                                                                                        0
                                              <100,000                ≥100,000                                                        <50        50–200       >200
                                           Baseline viral load (copies/mL)                                                         Baseline CD4 cell count (cells/mm3)
                                     N=      226          226        117        120                                           N=     30     30   111   118   202 198
                                                   †Chi   square analysis
                                                ARTEMIS: Responses by
                                                 LPV/r dosing schedule
                                     100
Patients with VL <50 copies/mL (%)




                                                                                                                84
                                                                      81
                                                 78
                                      80
                                                                                           71


                                      60


                                      40


                                      20


                                      0
                                                LPV/r            LPV/r* bid            LPV/r* qd            DRV/r qd
                                           N=    346                  267                  52                  343


                                                *27 patients receiving LPV/r bid and qd during the study were excluded from this analysis
           ARTEMIS: Median change in absolute
           CD4 cell count to Week 48 (ITT-NC=F)
                                  150
                                                                                        141 cells/mm3
Median change in CD4 cell count




                                                                                        137 cells/mm3
   from baseline (cells/mm3)




                                  120
                                                                              DRV/r qd (N=343)
                                                                              LPV/r qd or bid (N=346)
                                   90


                                   60


                                   30


                                    0
                                        2 4   8   12 16       24         36        48
                                                          Time (weeks)
      ARTEMIS: Virologic failure (VF) and
          emergence of mutations

                                               DRV/r qd                  LPV/r qd or bid
                                                (N=343)                        (N=346)

VF (> 50 cpm)                                       34 (10%)                    49 (14%)

VF (> 400 cpm)                                      11 (3%)                      18 (5%)
Paired baseline and VF
genotype available                                  10                           18

IAS-USA PI RAMS                                       0                           1*

IAS-USA NRTI RAMs                                    1†                           2†
                                                                †M184                  *A71T, V77I
VF by TLOVR


                 *IAS-USA mutations, Fall 2006; Johnson et al. Topics in HIV Medicine. 2006; 14:125-130
      ARTEMIS: Grade 2–4 adverse events

                                       DRV/r qd                 LPV/r qd or bid
 Gr 2–4 AEs† ≥2%
 incidence, n (%)                      (N=343)                       (N=346)
 GI (all AEs)                              23 (7)                      47 (14)    p<0.01

       Diarrhea                            14 (4)                      34 (10)    p<0.05
       Nausea                               6 (2)                      10 (3)
 Rash (all types)                           9 (3)                        4 (1)
†At   least possibly related to study drug, excluding laboratory-related events


• No renal SAEs and no treatment discontinuations due to renal AEs
         ARTEMIS: Grade 2–4 laboratory
                abnormalities

Grade 2–4 laboratory abnormalities                           DRV/r qd          LPV/r qd or bid
≥2% incidence, n (%)                                         (N=343)              (N=346)

  Alanine aminotransferase                                     29 (8)                35 (10)
  Aspartate aminotransferase                                   32 (9)                31 (9)
  Hyperglycemia                                                22 (6)                23 (7)
  Pancreatic amylase                                           23 (7)                17 (5)
  Pancreatic lipase                                              6 (2)                 6 (2)

  Total cholesterol                                            44 (13)               78 (23)
  Low-density lipoprotein                                      44 (13)                36 (11)
  Triglycerides                                                10 (3)                 38 (11)

     No significant changes in calculated creatinine clearance between baseline and Week 48 visits
                                          ARTEMIS: Mean fasting lipid levels over time
                                          ng/mL                                         mM
                                          300          Mean triglycerides                3.5                                                          Total cholesterol/HDL ratio
                                                                                                                                         5.5




                                                                                               Mean total cholesterol/HDL ratio (± SE)
Mean triglyceride concentration ( ± SE)




                                                        DRV/r qd (n=343)                                                                                       DRV/r qd (n=343)
                                          250           LPV/r qd or bid (n=346)          2.9                                             5.0                   LPV/r qd or bid (n=346)



                                                                                                                                         4.5
                                          200                                            2.3


                                                                                                                                         4.0

                                          150                                            1.7
                                                                                                                                         3.5



                                          100                                            1.1                                             3.0
                                                  2 4 8 12 16    24      36       48                                                                 2 4 8 12 16     24      36          48
                                                            Time (weeks)

           DRV/r n= 343                                         320               306                                                          343                 320                   305
           LPV/r n= 346                                         313               301                                                          346                 313                   301


                                                               = NCEP cut-off
               ARTEMIS: DRV plasma concentrations
                    for DRV/r 800mg/100mg
                          10,000
DRV plasma conc (ng/mL)




                           1,000




                            100
                                       EC50 = 55 ng/mL for wild-type virus
                                       (adjusted for protein binding)

                              10
                                                                                             Ctrough
                                   0        4        8       12      16      20   24
                                                                                                       36
                                                   Time post-dose (hours)
                                                PK substudy – week 4 data             Population PK study
                                                    (mean ± SD; N=9)               (median, IQR, range; N=335)
                ARTEMIS: Conclusions
• The use of once-daily DRV/r 800/100mg + TDF/FTC in
  treatment-naïve patients:
  – resulted in excellent virologic and immunologic responses
  – provided suitable exposure in all patients
  – was well tolerated, with a favorable safety profile

• In comparison to the LPV/r arm* in treatment-naïve
  patients:
  – For efficacy, DRV/r 800/100mg qd was non-inferior in the
    overall population, and superior in patients with high VL
  – DRV/r had lower incidence of common GI toxicities and
    triglyceride elevations


     *LPV/r arm included: LPV/r 400/100mg bid or 800/200mg qd, capsule and tablet formulations
        ARTEMIS: Acknowledgments
• The patients and their families for their participation and support during the study
• TMC114-C211 study team and the investigators and co-investigators:

Argentina: Waldo Belloso, Liiana Calanni, Lidia Cassetti,   Panama: Amalio Rodriguez, Nestor Sosa
Luisa De Wouters, Marcelo Losso                             Puerto Rico: Javier Morales Ramirez, Carmen Zorrilla-
Australia: Mark Bloch, David Cooper, Dominic Dwyer,         Maldonado
Robert Finlayson, Julian Gold, Mark Kelly, Cassy Workman    Russia: Natalia Dushkina, Oleg Kozyrev, Valeriy Kulagin,
Austria: Armin Rieger and Norbert Vetter                    Alexander Pronin, Vladimir Rafalsky, Oleg Romanenko,
Belgium: Nathan Clumeck, Jean-Christophe Goffard,           Elena Vinogradova, Evgeniy Voronin, Alexey Yakovlev
Beatrjs Van der Gucht, Eric Van Wijngaerden                 Singapore: Lian Lim Poh
Canada: Joss Dewet, Don Kilby, Patrice Junod, Chris         South Africa: Ezio Baraldi, Jan Fourie, Prudence Ive,
Tsoukas, Sharon Walmsley                                    Lerato Mohapi, Jennifer Pitt
Chile: Juan Ballesteros, Rebeca Northland                   Spain: Buenaventura Clotet, Pere Domingo
Costa Rica: Gisela Herrera, Iris Perez                      Switzerland: Milos Opravil
Denmark: Jan Gerstoft, Lars Mathiesen, Henrik Nielsen       Taiwan: Jen-Hsien Wang, Su Pen Yang
France: Micelle Bentata, Laurent Cotte, Pierre              Thailand: Ploenchan Chetchotisakd, Winai
Dellamonica, Pierre-Marie Girard, Christine Katlama,        Ratanasuwan, Kiat Ruxrungtham, Khuanchai
Thierry Prazuck, Dominique Salmon, Patrick Yeni             Supparatpinyo
Germany: Keikawus Arasteh, Gerd Fätkenheuer, Frank-         United Kingdom: Martin Fisher, Mark Nelson, Chloe
Detlef Goebel, Thomas Harrer, Hans Jaeger, Joerg-Andres     Orkin, Jonathan Weber
Rump, Dieter Schuster, Albrecht Stoehr, Jan Van Lunzen      United States: Ben Barnett, Alfred Burnside, Thomas
Greece: George Chrysos                                      Campbell, Philippe Chiliade, Amy Colson, Edwin
Guatemala: Eduardo Arathoon, Carlos Mejia-Villatoro         DeJesus, Richard Elion, Walford Fessel, Lucia Flamm,
Italy: Adriano Lazzarin, Anna Maria Orani                   Dushyantha Jayaweera, Peter Kadlecik, Homayoon
Malaysia: Christopher Lee                                   Khanlou, Lucia Martinez, David McDonough, Anthony
Mexico: Jaime Andrade-Villanueva, Gustavo Reyes-Teran,      Mills, Karam Mounzer, Robert Myers, Jeffrey Nadler,
Juan Sierra-Madero, Angelina Villasis-Keever                Brian Onbirbak, Roberto Ortiz, Kristen Patterson, Daniel
                                                            Pearce, Gerald Pierone, Jayashree Ravishankar, Afsoon
                                                            Roberts, Barry Rodwick, Stefan Schneider, Michael
                                                            Sension, Paul Skolnik, Aimee Wilkin, Michael Wohlfeiler,
                                                            Bienvenido Yangco                    Supported by Tibotec

								
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