48 week lipid and glucoserelated safety profile of darunavirritonavir in treatmentexperienced, paedi

1
48 week lipid- and glucose-related safety profile
of darunavir/ritonavirin treatment-experienced,p
aediatric 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

1Chris Hani Baragwanath Hospital, University of
the Witwatersrand, Johannesburg, South Africa
2Hospital Dos Servidores Do Estado, Rio De
Janeiro, Brazil3Hospital Geral De Nova Iguacu -
HGNI DST/AIDS, Nova Iguacu, Brazil4Universidade
Federal De Minas Gerais, Belo Horizonte, Brazil
5Tibotec BVBA, Mechelen, Belgium 6Hôpital Necker
Enfants Malades, Paris, France
2
DELPHI study design

• Phase II, open-label, multicentre
• Final efficacy and safety results presented
  previously1
• 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

• 617 years old
• HAART 12 weeks
• HIV RNA 1,000 copies/mL
• N80

DRV 1119mg/kg ritonavir 1.52.5mg/kg bid
OBR 2 NRTIs/NNRTIs/ENF
Patients received DRV as 75mg and 300mg tablets
20lt30kg DRV/r 375/50mg bid (n20) 30lt40kg
DRV/r 450/60mg bid (n24) 40kg DRV/r 600/100mg
bid (n36)
1Blanche S, et al. 48th ICAAC/46th IDSA 2008.
Abstract H-894 DELPHI Darunavir EvaLuation in
Pediatric, HIV-Infected, treatment-experienced
patientsHAART highly active antiretroviral
therapy DRV/r darunavir with low-dose
ritonavir OBR optimised background regimen
ENF enfuvirtide
3
Baseline demographics anddisease characteristics
CDC Centers for Disease Control and Prevention
SD standard deviation
4
Summary of antiretroviralsused at screening
(N80)
3TC
ABC
AZT
NRTIs
d4T
ddI
TDF
FTC
EFV
NNRTIs
NVP
LPV
SQV
APV
TPV
PIs
ATV
NFV
IDV
ENF
0
10
20
30
40
50
60
70
Patients who had used drug at screening ()
PIs protease inhibitors
5
Treatment-emergent lipid and glucose
abnormalities Week 48 analysis
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 cholesteroland LDL Based on
age-specific normal limits
LDL low-density lipoprotein HDL high-density
lipoprotein
6
Mean blood glucose levels at baseline and Week
48 (N80)
5.6
100
p 0.77
80
4.4
Normal values
60
3.3
Mean concentration (mmol/L SE)
Mean concentration (mg/dL SE)
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
7
Mean lipid levels at baselineand Week 48
250
2.8
plt0.01
200
2.3
150
1.7
Mean concentration (mmol/L SE)
Mean concentration (mg/dL SE)
1.1
100
0.6
50
0.0
0
Triglycerides
SI unit scales are different due to different
conversion factors (0.0113 for triglycerides and
0.0259 for cholesterolCentral laboratory normal
lipid values according to age neonates up to 17
years old) Triglycerides 148mg/dL or
1.67mmol/LTotal cholesterol 212mg/dL or
5.61mmol/L HDL 74mg/dL or 1.91mmol/L LDL130
mg/dL or 3.36mmol/L
8
Mean triglyceride levelsto Week 48
Normal value
5.0
400
4.0
300
3.0
At baseline, 35/80 (44) had levels above the
normal value
At Week 48, 16/73 (22) had levels above the
normal value
Mean concentration (mmol/L SE)
Mean concentration (mg/dL SE)
200
2.0
100
At Week 24, 15/76 (20) had levels above the
normal value
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
9
Association of baseline triglyceride level with
use of LPV/r at screening
Fisher exact test

• Almost half of all patients (36/80, 45) were
  receiving LPV/r at screening
• For all other lipid parameters, mean baseline
  values were within the normal ranges

LPV/r lopinavir with low-dose ritonavir
10
Mean triglyceride levels to Week 48 in patients
using/not using LPV/r at screening
Patients using LPV/r at screening
Patients not using LPV/r at screening
5.0
400
4.0
300
3.0
Mean concentration (mmol/L SE)
Mean concentration (mg/dL SE)
200
2.0
Normal values
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
11
Summary Week 48 lipid- and glucose-related
safety analysis of DELPHI

• In treatment-experienced, HIV-1-infected children
  and adolescents aged 617 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 (plt0.01)
• 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

12
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, Patricia Coll, Alejandro
  Krolewiecki, Lorena Abusamra, Patricia Patterson,
  Omar Sued, Carina Cesar, Débora Mecikovsky,
  Valeria Blumeti, Claudio Cantisano, Marcela
  Candi, Patricia Trinidad, Fernando Vesperoni
• Brazil Esaú João, Marisa Mussi-Pinhata, José
  Henrique Pilotto, Jorge Pinto, Ana Valeria
  Cordovil, Priscila Mazucanti, Tania de Souza
  Brum, Luciano Torres de Sousa, Marilia Oliviera,
  Ivete Gomes, Jorge Eurico Ribeiro, Maria Célia
  Cervi, Adriana Aparecida Tiraboschi, Márcia de
  Lima Isaac, Bento Negrini, Flavia Ferreira,
  Fabiana Kakehasi, Ana Lucia Nigeuira Diniz,
  Martins Lilian Diniz, Aparecida Araujo Claudete,
  Maria Letícia Cruz, Eduarda Gusmao, Mariza
  Saavedra
• Canada Normand Lapointe, Stanley E Read, Sean
  Ari Bitnun, Jason Brophy, Mireille Lemay
• France Stéphane Blanche, Florence Veber-Parrenne
• Italy Carlo Giaquinto, Gianvincenzo Zuccotti,
  Nicola Principi, Jelena Bojanin, Laura Cesati,
  Susanna Esposito, Vania Giacomet, Laura
  Gualtieri, Alessandro Porta, Osvalda Rampon,
  Alessandra Viganò
• Romania Dan Duiculescu, Adrian Streinu Cercel,
  Claudia Simona Cambrea, Roxana Cernat, Ruxandra
  Draghicenoiu, Irina Magdalena Dumitru, Luminita
  Ene, Mariana Madarescu, Consuela Marcas,
  Cristiana Oprea, Sorin Petrea, Roxana Radoi,
  Sorin Rugina, Ana Maria Tudor

South Africa Razia Bobat, Mark Cotton, Tammy
Meyers, Mohenderan Archary, Claire Egbers,
Jonelle Howard, Lee Kleynhans, Delania Lawrence,
Carla Maisel, Dudu Malinga, I E Mong, Megan
Palmer, Helena Rabie, E J Smit, Heinrich C
Weber Spain Claudia Fortuny, M I De Jose,
Beatriz Larru, Antoni Noguera UK Rana
Chakraborty, Mike Sharland USA Sandra K
Burchett, Joseph A Church, Katherine Luzuriaga,
Richard Rutstein, Hans Spiegel, Andrew A Wiznia,
Ram Yogev, Jacobo A Abadi, Evan Anderson, Maskit
Bar-Meir, Tracey A Barnett, Ellen Chadwick,
Patricia C Coburn, Lawrence DAngelo, Serena E
Dee, Sally Discenza, Joanna Dobroszycki, Marion
Donahoe, Theresa M Dunaway, William Durbin,
Patricia P Dykstra, Ronald Ferdman, Patricia
Flynn, Aditya Gaur, Mindy A Golatt, Lynn Heald,
Carmell Hippias, Nanna Howlett, Preeti Jaggi,
Sandra Jones, Nancy Karthas, Ben Katz, Jennifer
Kershaw, Katherine Knapp, Catherine Kneut, Lynne
Lewis, Latania Logan, Charlotte Mao, Kenneth
McIntosh, Carla McKinley, Richard Moriarty, Peck
Y Ong, Nehali Patel, Shoshana Peyser, Maura E
Porricolo, Kristin Ragucci, Natella Rakhmanina,
Tamara Rakusan, Michail G Rosenberg, Cathryn
Samples, John L Sullivan, Amy Talsky, Tina Tan,
Carol A Vincent
Editorial support provided by Gardiner-Caldwell
Communications This support was funded by Tibotec