48 week lipid- and glucose-related safety profile of by duw14213


									48 week lipid- and glucose-related
safety profile of darunavir/ritonavir
     in treatment-experienced,
   paediatric patients in DELPHI
     Tammy Meyers,1 Esau Joao,2 José Henrique Pilotto,3
       Jorge Pinto,4 Ben Van Baelen,5 Ludo Lavreys,5
       Sabrina Spinosa-Guzman,5 Stéphane Blanche6
   1ChrisHani Baragwanath Hospital, University of the Witwatersrand, Johannesburg,
      South Africa; 2Hospital Dos Servidores Do Estado, Rio De Janeiro, Brazil;
       3Hospital Geral De Nova Iguacu - HGNI DST/AIDS, Nova Iguacu, Brazil;
    4Universidade Federal De Minas Gerais, Belo Horizonte, Brazil; 5Tibotec BVBA,

         Mechelen, Belgium; 6Hôpital Necker Enfants Malades, Paris, France
               DELPHI: study design
• Phase II, open-label, multicentre
• Final efficacy and safety results presented previously1
                                                                     48 weeks
• 6–17 years old
                                              DRV 11–19mg/kg + ritonavir 1.5–2.5mg/kg bid
• HAART ≥12 weeks
                                                        + OBR: ≥2 NRTIs/NNRTIs/ENF
• HIV RNA ≥1,000 copies/mL
                                           Patients received DRV as 75mg and 300mg tablets
• N=80
                                                   20–<30kg: DRV/r 375/50mg bid (n=20)
                                                   30–<40kg: DRV/r 450/60mg bid (n=24)
                                                    ≥40kg: DRV/r 600/100mg bid (n=36)

• Lipid and glucose safety profile are described
  –      patients fasted ≥10 hours before blood sampling at baseline,
         Week 24 and 48
  –      no patients received lipid-lowering agents
                                            1Blanche S, et al. 48th ICAAC/46th IDSA 2008. Abstract H-894
                DELPHI = Darunavir EvaLuation in Pediatric, HIV-Infected, treatment-experienced patients
                   HAART = highly active antiretroviral therapy; DRV/r = darunavir with low-dose ritonavir;
                                                OBR = optimised background regimen; ENF = enfuvirtide
      Baseline demographics and
        disease characteristics
Demographics                                                             N=80
Male, n (%)                                                             57 (71)
Age, n (%)
 6–<12 years                                                            24 (30)
 12–17 years                                                            56 (70)
Perinatal infection, n (%)                                              62 (78)
CDC class C, n (%)                                                      40 (50)

Disease characteristics                                                   N=80
Mean HIV-1 RNA, log10 copies/mL (SD)                                 4.64 (0.80)
Median CD4 cell count, cells/mm3 (range)                           330 (6–1505)
Median CD4 cell count, % (range)                                      17 (1–47)
                     CDC = Centers for Disease Control and Prevention; SD = standard deviation
          Summary of antiretrovirals
           used at screening (N=80)
 NRTIs    d4T
                 0   10      20         30          40         50            60           70
                          Patients who had used drug at screening (%)
                                                                    PIs = protease inhibitors
 Treatment-emergent lipid and glucose
    abnormalities: Week 48 analysis
 Grade 2–4* laboratory parameter, n (%)                                                   N=80
 Mean exposure (weeks)                                                                     60.3
 Triglycerides                                                                           1 (1.3)
 Total cholesterol                                                                     11 (13.8)
 LDL                                                                                   11 (13.8)
 Hyperglycaemia                                                                         9 (11.3)
 Non-graded laboratory parameter, n (%)                                                   N=80
 HDL abnormal, above the upper normal limit‡                                             1 (1.3)
 HDL abnormal, below the lower normal limit‡                                             5 (6.3)
*Based on the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Paediatric Adverse Events
2004, which does not have a grade 1 classification for triglycerides and grade 4 for total cholesterol
and LDL; ‡Based on age-specific normal limits

                                                  LDL = low-density lipoprotein; HDL = high-density lipoprotein
                                      Mean blood glucose levels
                                    at baseline and Week 48 (N=80)
                                    100                             p = 0.77                                          5.6

                                                                                                                              Mean concentration (mmol/L [± SE])
Mean concentration (mg/dL [± SE])

                                    80                                                                                4.4
                                                                 Normal values

                                    60                                                                                3.3

                                    40                                                                                2.2

                                    20                                                                                1.1

                                      0                                                                               0.0
                                                  Baseline                            Week 48

                                          Central laboratory normal glucose values according to age [neonates up to 17 years old]):
                                                                                       80mg/dL or 4.4mmol/L; SE = standard error
                                                 Mean lipid levels at baseline
                                                        and Week 48
                                                                                                                                                 Baseline           Week 48        Normal values
                                    250                     2.8                                                                            250                                                     6.5                                                     5.0
                                             p<0.01                                                                                                     p<0.05           p<0.001      p<0.05                                                                          p=0.42

                                    200                     2.3                                                                            200                                                     5.2                                                     4.0

                                                                                                                                                                                                         Mean concentration (mmol/L [± SE])
                                                                  Mean concentration (mmol/L [± SE])
Mean concentration (mg/dL [± SE])

                                                                                                       Mean concentration (mg/dL [± SE])

                                    150                     1.7                                                                            150                                                     3.9                                                     3.0

                                                                                                                                                                                                                                              Mean ratio
                                    100                     1.1                                                                            100                                                     2.6                                                     2.0

                                    50                      0.6                                                                            50                                                      1.3                                                     1.0

                                      0                     0.0                                                                              0                                                     0.0                                                      0
                                          Triglycerides                                                                                                 Total             LDL          HDL                                                                       Total cholesterol/
                                                                                                                                                      cholesterol        direct                                                                                     HDL ratio
                                                            SI unit scales are different due to different conversion factors (0.0113 for triglycerides and 0.0259 for cholesterol
                                              Central laboratory normal lipid values according to age [neonates up to 17 years old]); Triglycerides: 148mg/dL or 1.67mmol/L
                                                                  Total cholesterol: 212mg/dL or 5.61mmol/L; HDL: 74mg/dL or 1.91mmol/L; LDL:130 mg/dL or 3.36mmol/L
                                          Mean triglyceride levels
                                                to Week 48
                                                                         Normal value

                                                                                                                                  Mean concentration (mmol/L [± SE])
Mean concentration (mg/dL [± SE])

                                              At baseline, 35/80 (44%)
                                                                                         At Week 48, 16/73 (22%)
                                                had levels above the
                                    200             normal value
                                                                                           had levels above the
                                                                                              normal value                2.0

                                    100                     At Week 24, 15/76 (20%) had                                   1.0
                                                            levels above the normal value

                                     0                                                                                    0.0
                                          0                             24                                    48
                                                                   Time (weeks)
                                                    Central laboratory normal lipid values according to age [neonates up to 17 years old])
                                                                                                   Triglycerides: 148mg/dL or 1.67mmol/L
     Association of baseline triglyceride
     level with use of LPV/r at screening
                      Patients using     Patients not
                         LPV/r at       using LPV/r at
                        screening         screening
 Incidence, n (%)         (n=36)            (n=44)                  p value*
 Abnormal                21 (58)            14 (32)                   0.0238
 triglyceride level
 (>148mg/dL or
*Fisher exact test

• Almost half of all patients (36/80, 45%) were receiving LPV/r at
• For all other lipid parameters, mean baseline values were within
  the normal ranges
                                           LPV/r = lopinavir with low-dose ritonavir
  Mean triglyceride levels to Week 48 in
patients using/not using LPV/r at screening
                                                 Patients using LPV/r                 Patients not using
                                                 at screening                         LPV/r at screening

                                                                                                                             Mean concentration (mmol/L [± SE])
 Mean concentration (mg/dL [± SE])


                                                                                        Normal values                 2.0

                                     100                                                                             1.0

                                      0                                                                               0.0
                                           0                       24                                    48
                                                              Time (weeks)
                                               Central laboratory normal lipid values according to age [neonates up to 17 years old])
                                                                                              Triglycerides: 148mg/dL or 1.67mmol/L
Summary: Week 48 lipid- and glucose-
  related safety analysis of DELPHI
• In treatment-experienced, HIV-1-infected children and
  adolescents aged 6–17 years
  –   the most frequent laboratory abnormalities were increased
      total cholesterol and LDL (13.8% for both)
  –   the most pronounced change was a significant reduction in
      mean triglycerides from baseline to Week 48 (p<0.01)
      •   this decrease was most apparent in patients switching from LPV/r
  –   small but statistically significant mean increases in total
      cholesterol, LDL and HDL were observed
  –   no statistically significant changes in total cholesterol/HDL
      ratio and mean glucose were seen

• DRV/r has a favourable lipid and glucose safety
  profile in treatment-experienced, HIV-1-infected
  paediatric patients
             DELPHI: acknowledgements
•     The children, young people and their families for their participation and
      support during the study
•     The DELPHI (TMC114-C212) principal investigators and their staff
Argentina: Graciela Barboni, Rosa Bologna, Pedro Cahn, Vera Giraudi,         South Africa: Razia Bobat, Mark Cotton, Tammy Meyers,
Patricia Coll, Alejandro Krolewiecki, Lorena Abusamra, Patricia Patterson,   Mohenderan Archary, Claire Egbers, Jonelle Howard, Lee Kleynhans,
Omar Sued, Carina Cesar, Débora Mecikovsky, Valeria Blumeti,                 Delania Lawrence, Carla Maisel, Dudu Malinga, I E Mong,
Claudio Cantisano, Marcela Candi, Patricia Trinidad, Fernando Vesperoni      Megan Palmer, Helena Rabie, E J Smit, Heinrich C Weber
Brazil: Esaú João, Marisa Mussi-Pinhata, José Henrique Pilotto,              Spain: Claudia Fortuny, M I De Jose, Beatriz Larru, Antoni Noguera
Jorge Pinto, Ana Valeria Cordovil, Priscila Mazucanti, Tania de Souza        UK: Rana Chakraborty, Mike Sharland
Brum, Luciano Torres de Sousa, Marilia Oliviera, Ivete Gomes,
Jorge Eurico Ribeiro, Maria Célia Cervi, Adriana Aparecida Tiraboschi,       USA: Sandra K Burchett, Joseph A Church, Katherine Luzuriaga,
Márcia de Lima Isaac, Bento Negrini, Flavia Ferreira, Fabiana Kakehasi,      Richard Rutstein, Hans Spiegel, Andrew A Wiznia,
Ana Lucia Nigeuira Diniz, Martins Lilian Diniz, Aparecida Araujo Claudete,   Ram Yogev, Jacobo A Abadi, Evan Anderson, Maskit Bar-Meir,
Maria Letícia Cruz, Eduarda Gusmao, Mariza Saavedra                          Tracey A Barnett, Ellen Chadwick, Patricia C Coburn, Lawrence
                                                                             D’Angelo, Serena E Dee, Sally Discenza, Joanna Dobroszycki,
Canada: Normand Lapointe, Stanley E Read, Sean Ari Bitnun,                   Marion Donahoe, Theresa M Dunaway, William Durbin, Patricia P
Jason Brophy, Mireille Lemay                                                 Dykstra, Ronald Ferdman, Patricia Flynn, Aditya Gaur, Mindy A
France: Stéphane Blanche, Florence Veber-Parrenne                            Golatt, Lynn Heald, Carmell Hippias, Nanna Howlett, Preeti Jaggi,
Italy: Carlo Giaquinto, Gianvincenzo Zuccotti, Nicola Principi,              Sandra Jones, Nancy Karthas, Ben Katz, Jennifer Kershaw,
Jelena Bojanin, Laura Cesati, Susanna Esposito, Vania Giacomet,              Katherine Knapp, Catherine Kneut, Lynne Lewis, Latania Logan,
Laura Gualtieri, Alessandro Porta, Osvalda Rampon, Alessandra Viganò         Charlotte Mao, Kenneth McIntosh, Carla McKinley, Richard Moriarty,
                                                                             Peck Y Ong, Nehali Patel, Shoshana Peyser, Maura E Porricolo,
Romania: Dan Duiculescu, Adrian Streinu Cercel, Claudia Simona               Kristin Ragucci, Natella Rakhmanina, Tamara Rakusan, Michail G
Cambrea, Roxana Cernat, Ruxandra Draghicenoiu, Irina Magdalena               Rosenberg, Cathryn Samples, John L Sullivan, Amy Talsky, Tina Tan,
Dumitru, Luminita Ene, Mariana Madarescu, Consuela Marcas,                   Carol A Vincent
Cristiana Oprea, Sorin Petrea, Roxana Radoi, Sorin Rugina,
Ana Maria Tudor

                                                                       Editorial support provided by Gardiner-Caldwell Communications
                                                                                                    This support was funded by Tibotec

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