Transcript ARTEMIS: Efficacy and safety of lopinavir (BID vs QD) and

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
1Chris
Hani 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
• HAART ≥12 weeks
DRV 11–19mg/kg + ritonavir 1.5–2.5mg/kg bid
+ OBR: ≥2 NRTIs/NNRTIs/ENF
• HIV RNA ≥1,000 copies/mL
• N=80
Patients received DRV as 75mg and 300mg tablets
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
12–17 years
24 (30)
56 (70)
Perinatal infection, n (%)
62 (78)
CDC class C, n (%)
40 (50)
Disease characteristics
Mean HIV-1 RNA, log10 copies/mL (SD)
Median CD4 cell count, cells/mm3 (range)
Median CD4 cell count, % (range)
N=80
4.64 (0.80)
330 (6–1505)
17 (1–47)
CDC = Centers for Disease Control and Prevention; SD = standard deviation
Summary of antiretrovirals
used at screening (N=80)
NRTIs
NNRTIs
PIs
3TC
ABC
AZT
d4T
ddI
TDF
FTC
EFV
NVP
LPV
SQV
APV
TPV
ATV
NFV
IDV
ENF
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
LDL
Hyperglycaemia
11 (13.8)
11 (13.8)
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)
5.6
p = 0.77
4.4
80
Normal values
60
3.3
40
2.2
20
1.1
0
0.0
Baseline
Mean concentration (mmol/L [± SE])
Mean concentration (mg/dL [± SE])
100
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
2.8
250
2.3
150
1.7
100
1.1
50
0
Triglycerides
5.0
6.5
p<0.05
p<0.001
p<0.05
p=0.42
5.2
150
3.9
100
2.6
0.6
50
1.3
1.0
0.0
0
0.0
0
Total
cholesterol
LDL
direct
HDL
4.0
Mean ratio
Mean concentration (mg/dL [± SE])
200
Mean concentration (mmol/L [± SE])
Mean concentration (mg/dL [± SE])
p<0.01
200
Normal values
Mean concentration (mmol/L [± SE])
250
Week 48
3.0
2.0
Total cholesterol/
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
5.0
400
4.0
300
3.0
At baseline, 35/80 (44%)
had levels above the
normal value
200
100
At Week 48, 16/73 (22%)
had levels above the
normal value
At Week 24, 15/76 (20%) had
levels above the normal value
2.0
1.0
0.0
0
0
24
Time (weeks)
Mean concentration (mmol/L [± SE])
Mean concentration (mg/dL [± SE])
Normal value
48
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
Incidence, n (%)
Abnormal
triglyceride level
(>148mg/dL or
1.67mmol/L)
Patients using
LPV/r at
screening
(n=36)
Patients not
using LPV/r at
screening
(n=44)
p value*
21 (58)
14 (32)
0.0238
*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
Mean concentration (mg/dL [± SE])
Patients using LPV/r
at screening
Patients not using
LPV/r at screening
5.0
400
4.0
300
3.0
200
2.0
Normal values
100
1.0
0
0.0
0
24
Time (weeks)
Mean concentration (mmol/L [± SE])
Mean triglyceride levels to Week 48 in
patients using/not using LPV/r at screening
48
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 glucoserelated 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,
Patricia Coll, Alejandro Krolewiecki, Lorena Abusamra, Patricia Patterson,
Omar Sued, Carina Cesar, Débora Mecikovsky, Valeria Blumeti,
Claudio Cantisano, Marcela Candi, Patricia Trinidad, Fernando Vesperoni
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
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
Spain: Claudia Fortuny, M I De Jose, Beatriz Larru, Antoni Noguera
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
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
D’Angelo, 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