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?.