3TCABC maintains virological superiority over ZDV3TC and ZDVABC beyond 5 years in children: the PENT - PowerPoint PPT Presentation
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3TCABC maintains virological superiority over ZDV3TC and ZDVABC beyond 5 years in children: the PENT
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DM Gibb, H Green, Y Saidi, D Pillay, A Compagnucci, L Harper, AS Walker, G ... Kelly*; PHL Regional Virus Laboratory, Bristol: O Caul ; Ninewells Hospital and ... – PowerPoint PPT presentation
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Title: 3TCABC maintains virological superiority over ZDV3TC and ZDVABC beyond 5 years in children: the PENT
1
3TC\ABC maintains virological superiority over
ZDV\3TC and ZDV\ABC beyond 5 years in children
the PENTA 5 trial
DM Gibb, H Green, Y Saidi, D Pillay, A
Compagnucci, L Harper, AS Walker, G
Castelli-Gattinara, M della Negra, J levy, F
Candeias, K Butler, C Feiterna-Sperline, U
Wintergerst, C Giaquinto on behalf of
Paediatric European Network for the Treatment of
AIDS (PENTA)
2
Background
- Few randomised trials in untreated children
comparing different ART combinations.
The Lancet 2002 359, 733-740
3
Baseline characteristics
- 126 children followed after 48 weeks
- 36 ZDV\3TC, 44 ZDV\ABC, 46 3TC\ABC
- 2 died/lost to follow-up within 2 weeks of
randomisation - 56 boys
- 46/42 white/black African
- Median age 5.4 years
- Mean HIV-1 RNA 5.1 log10 copies/ml
- Median CD4 22
- 9 prior AIDS
Due to minor imbalances in baseline
characteristics, all analyses are adjusted for
age, HIV-1 RNA and CD4 at baseline, plus
allocation to NFV or placebo
4
Follow-up and clinical events
- Median follow-up 5.8 years (range 3.1 to 7.8
years) - only 18 (14) children have less than 5 years
follow-up - 6 children had new AIDS events during 702 child
years of follow-up - 4 before and 2 after 48 weeks
- No recurrent AIDS events
- 1 child died at 3 years (Hodgkins lymphoma)
- ? 94 new AIDS-free survival at 5 years in all
arms
5
NRTIs to 5 years
- Proportion of child-time spent taking randomised
NRTIs was around 85 in the first 2.5 years of
the trial - From 2.5 to 5 years, the proportion still taking
NRTIs was lower in the ZDV groupsZDV\3TC 61ZDV
\ABC 543TC\ABC 69 - Changes in randomised NRTIs were mainly to ddI or
d4T - 3TC\ABC arm
- more time on randomised NRTIs
- exposed to fewer number of drugs
- fewer switches to 2nd line therapy
6
ART at 5 years
- By 5 years, 50 (63/126) of children were still
taking randomised NRTIs
7
ART at 5 years
- By 5 years, 50 (63/126) of children were still
taking randomised NRTIs
8
Change in HIV-1 RNA
- p-value 0.03 0.03
0.03 0.01 0.001 - Overall strong evidence of a difference between
treatment arms (plt0.001) - No evidence this varied over time (p0.5)
All analyses intention-to-treat
9
HIV-1 RNA suppression
lt400 copies/ml
lt50 copies/ml
- Overall strong evidence of a difference between
treatment arms (p0.003 and 0.006
respectively) - No evidence this varied over time (p0.4 and
0.1 respectively)
All analyses intention-to-treat
10
Growth
Height-for-age
Weight-for-age
- Overall strong evidence of a difference between
treatment arms (p0.001 and 0.04
respectively) - Trend towards increasing benefit from 3TC\ABC
in weight-for-age (p0.09), but not for
height-for-age (p0.6) - There was no difference in mean CD4 at 5 years
(33, 30 and 33, p0.2)
All analyses intention-to-treat
11
Dual NRTI
- 24 children randomised to NFV placebo
- At 5 years, 7 (29) were still taking dual NRTI
therapy - 0/7 (0) ZDV\3TC
- 3/11 (27) ZDV\ABC
- 4/6 (83) 3TC\ABC
- 4 children had had HIV-1 RNA lt400 copies/ml
throughout - 1/3 ZDV\ABC
- 3/4 3TC\ABC
- 3 children had HIV-1 RNA lt4000 copies/ml
12
Resistance
- 16 children had 2 or more resistance tests after
baseline whilst still on randomised NRTIs,
despite continuing viral replication. - ZDV\3TC (n4)
- all developed 184V by 1 year
- then developed TAMs (41L, 67N, 70R, 210W, 215Y)
maintained 184V - ZDV\ABC (n6)
- 4 maintained wild-type virus through 3 - 4.5
years - 2 developed TAMs at 3/3.5 years (41L, 67N, 70R,
210W, 215F/Y, 219Q) - 3TC\ABC (n6)
- 4 had non-TAM mutations by year 1 (65R, 74V,
115F, 184V) - 2 maintained non-TAMs, 1 lost all mutations and 1
developed TAMs - 2 M184V only by 5 years
13
Conclusions
- Children do well clinically and immunologically
on all regimens - very few AIDS events over 5 years
- 3TC\ABC
- Long-term sustained virological superiority
- Short-term benefits in terms of growth persist
- Lower rates of switching with detectable viral
load - Order and pattern of resistance dependent on
combination of NRTIs used - 3TC\ABC is an excellent first-line NRTI backbone
- can be taken once daily in children gt 3 years
- same small volume liquids
- fixed dose combination scored baby pill?
14
Acknowledgements
- We thank all the children, families and staff
from all the centres participating in the PENTA 5
Trial - Medical Research Council Clinical Trials Unit,
UK A Babiker, L Buck, J Darbyshire, L Farrelly,
DM Gibb, H Green, L Harper, D Johnson, P
Kelleher, A Newberry, A Poland, G Wait, AS Walker - INSERM SC10, FranceJP Aboulker, A Compagnucci,
M Debré, V Eliette, S Girard, S Leonardo,
Y Saidi - Executive Committee for PENTA 5JP Aboulker, A
Babiker, A Compagnucci, J Darbyshire, M Debré, M
Gersten (Agouron), C Giaquinto (chairperson), DM
Gibb, W Snowdon (GlaxoSmithKline)
15
Acknowledgements
- Participating Centres pharmacists, ?virologists
- Belgium Hôpital Saint Pierre, Brussels J Levy,
M Hainaut, A Peltier, S Carlier, G Zissis?.
Brazil Instituto de Infectologia Emilio Ribas,
São Paolo M Della Negra, W. Queiroz Fleury
Laboratories, São PaoloLP Feitosa?, D Oliveira?. - France Centre Hospitalier Universitaire, Nantes
F Mechinaud, V Reliquet, F Ballerau, A
Lepelletier, S Billaudel?, V Ferre?. Germany
Virchow-Klinikum, Humboldt-Universität zu Berlin
I Grosch-Wörner, R Weigel, K Seel, C
Feiterna-Sperling, D Ohlendorf, G Riße, C
Müller? Universitäts-Kinderklinik Düsseldorf V
Wahn, T Niehues, J Ndagijimana, G Horneff, S
Gudowius, N Vente? Universitäts-Kinderklinik
Eppendorf, Hamburg R Ganschow, G Englert.
Universitat zu Köln T Simon, R Vossen, H
Pfister? Universitäts-kinderkliniken, Munich U
Wintergerst, G Notheis, G Strotmann, S Schlieben.
Ireland Our Ladys Hospital for Sick Children,
Dublin K Butler, E Hayes, M O'Mara, J Fanning,
F Goggins, S Moriarty, M Byrne .Italy
Ospedale Regionale di Bolzano L Battisti
Spedali Civili, Brescia M Duse, S Timpano, E
Uberti, P Crispino, P Carrara, F Fomia, R
Schumacher, A. Manca? Ospedale Meyer, Florence
L Galli, M de Martino Istituto G Gaslini,
Genova F Fioredda, E Pontali, R Rosso Ospedale
Civile, Modena M Cellini, C Baraldi, M
Portolani?, M Meacci?, P Pietrosemoli?
Università di Napoli Federico II A Guarino, MI
Spagnuola, R Berni Canani, V Giacomet, P
Laccetti?, M Gobbo? Università di Padova C
Giaquinto, V Giacomet, R DElia, O Rampon, V
Balasso, A de Rossi?, M Zanchetta? IRCCS
Policlinico San Matteo, PaviaD Caselli, A
Maccabruni, E Cattaneo?, V Landini? Ospedale
Bambino Gesù, Rome G Castelli-Gattinara, S
Bernardi, A Krzysztofiak, C Tancredi, P Rossi?, L
Pansani? Università degli Studi di Torino E
Palomba, C Gabiano Ospedale S. Chiara, Trento A
Mazza, G Rossetti? Ospedale S. Bortolo, Vicenza
R Nicolin, A Timillero. Portugal Hospital de
Dona Estefania, Lisbon L Rosado, F Candeias, G
Santos, ML Ramos Ribeiro, MC Almeida, MH
Lourenço?, R Antunes? Spain Instituto de Salud
Carlos III, Madrid MJ Mellado Peña?, PM
Fontenlos, ML Carillo de Albornoz, P Martinez
Santos Hospital Son Dureta, Palma de Mallorca L
Ciria Calavia, J Dueñas Morales, J Serra
Devecchi, O Delgado, N Matamoros?. UK Bristol
Royal Hospital for Sick Children, BristolA Foot,
H Kershaw, C Kelly PHL Regional Virus
Laboratory, Bristol O Caul? Ninewells Hospital
and Medical School, Dundee W Tarnow-Mordi, J
Petrie, Alison McDowell, P McIntyre?, K
Appleyard? Ealing Hospital, Middlesex K Sloper,
V Shah, K Cheema, A Aali? Royal Edinburgh
Hospital for Sick Children, J Mok, R Russell, A
Brewster, N Richardson City Hospital,
Edinburgh S Burns? Great Ormond St Hospital
for Children NHS Trust, London D Gibb, V
Novelli, N Klein, L McGee, S Ewen, J Flynn, V
Yeung Kings College Hospital, London C Ball,
K Himid, D Nayagam, D Graham, S Hawkins, A
Barrie, K Stringer, S Jones, N Weerasooriya,
M Zuckerman?, P Bracken? Newham General
Hospital, London D Gibb, E Cooper, T Fisher, R
Barrie, S Liebeschuetz, S Wong, U Patel
(deceased) Royal Free Hospital, London V Van
Someren, K Moshal, S McKenna, L Perry, T
Gundlach? St Bartholemews Hospital, London J
Norman? St Georges Hospital, London M
Sharland, M Richardson, S Donaghy, S Storey, Z
Mitchla C Wells, J Booth? (deceased), A Shipp?
D Butcher? St Marys Hospital, London G
Tudor-Williams, H Lyall, J White, S Head, C
Walsh, C Hanley, S Campbell, S Lambers, K
O'Hara C Stainsby? St Thomas Hospital,
London G Du Mont, R Cross, T Solanki, S
Swanton, S OShea?, A Tilsey? University
College London Medical School S Kaye?
Childrens Hospital, Sheffield A Finn, S Choo, R
Lakshman, J Hobbs, L Barr Sheffield Public
Health Laboratory, Sheffield G Bell?, A Siddens?.
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