1. PLATO II Children Study (Pursuing LAter Treatment Options) Karina Butler Our Lady’s Children’s Hospital, Dublin, Ireland on behalf of the PLATO II Project Team of COHERE Triple class virologic failure (TCVF) in HIV-infected children

2. PLATO II Children A key challenge in the management of HIV infected children is to sustain viral suppression and maintain therapy options as they move though adolescence into adulthood Virologic failure of three drug classes during childhood could limit future treatment options Aim: To describe the incidence and predictors of virologic failure of the three original antiretroviral classes in infants and children, and to compare these findings to those in adults* * PLATO II Arch Intern Med 2010;170(5):410-419

3. PLATO II Children: Population Cohorts within COHERE Children < 16 years of age Perinatally infected ARV naïve or exposed to PMTCT only Initiated therapy from 1998 onwards

4. PLATO II children: Antiretroviral Therapy NNRTI + 2 NRTI NNRTI + 3 NRTI PI/r + 2 or 3 NRTI uPI + 2 or 3 NRTI 3 NRTIs 2 NRTIs 1 NNRTI 1 PI children Started with: TCVF*: *Triple class virologic failure = viral load >500 c/ml after 4 months of continued use of each drug class

5. PLATO II children: Comparison with adults NNRTI + 2 NRTI NNRTI + 3 NRTI PI/r + 2 or 3 NRTI uPI + 2 or 3 NRTI 3 NRTIs 2 NRTIs 1 NNRTI 1 PI/r NNRTI + 2 NRTI PI/r + 2 NRTI children adults (heterosexually acquired HIV) Started with: TCVF*: *Triple class virologic failure = viral load >500 c/ml after 4 months of continued use of each drug class

6. PLATO II Children (n=1007) From 8 cohorts from within COHERE _____________________________________ Country of Cohortn% ___________________________________________________________________________ UK & Ireland681 67.6 Spain108 10.7 Netherlands 84 8.3 France 727.1 Denmark 242.4 Italy 20.2 Belgium 10.1 ECS 353.5 _________________________________________________________________________________________

7. PLATO II Children: Baseline N=1007 51% male, 49% female 7% PMTCT exposure Year initiated ART 37% 1998-2000 36%2001-2003 27%2004-2007

8. PLATO II Children: Baseline N=1007 Age at start of ART (years) –35% <2y; 20% 2-4y; 26% 5-9y; 19% 10-15y Initial regimen –46%2 NRTIs + 1 NNRTI –9%3 NRTIs + 1 NNRTI –12%2 or 3 NRTIs + 1 PI/r –27%2 or 3 NRTIs + 1 uPI –5%3 NRTIs 21% had a previous AIDS diagnosis CD4% median (IQR) 15 (9-24) Viral load median (IQR) 5.1 log 10 c/ml (4.6-5.7)

9. TCVF in children 1007 children followed for median of 4.2 years (IQR: 2.4-6.5) 23.5% (237/1007) were triple class exposed 10.4% (105/1007) met criteria for TCVF, of whom 28% (29/105) never had VL ≤500 c/ml By Kaplan – Meier analysis the cumulative risk of TCVF by 5 years after starting ART was 12.0% (95% CI 9%-15%)

10. Incidence of TCVF in children Person-years983855698549408301210119 TCVF5222116151263 % still on ART97959390888178

11. Predictors of TCVF in children HR95% CIp Age at start of ART (years) <2 2-4 5-9 10-15 1.2 0.9 1 2.3 0.7-2.1 0.5-1.7 - 1.2-4.1 0.02 Pre-ART AIDS No Yes 1 1.4 - 0.9-2.3 0.14 Gender, year of starting ART, initial regimen, CD4% and viral load at ART initiation were not significant in multivariate analysis

12. TCVF in children vs. adults Restricted to children on NNRTI or boosted PI 686 children TCVF by 5 yrs after ART initiation was: 8.2% (95%CI 5%-11%) in children 4.2% (95% CI: 4%-5%) in adults* HR children vs adults: 2.2 (95% CI 1.6-3.0), p<0.001 HR excluding ages 10–15yr 1.7 (1.1-2.5) p=0.01 (adjusted for pre-ART AIDS and year starting ART) * PLATO II Arch Intern Med 2010;170(5):410-419

13. Summary ≈90% of HIV-infected children starting ART did not develop virologic failure to the 3 original drug classes over a median of 4 years follow-up Children who were older at ART initiation and those with AIDS had a higher risk of TCVF The rate of TCVF in children was significantly higher than in adults This trend persisted after excluding 10-15yr olds, suggesting that poor adherence in adolescence only partly explains the problem

14. Conclusions The rate of TCVF highlights the challenge of maintaining lifelong viral suppression in children There is continued need for strategies to promote optimal adherence among care givers, children and adolescents fixed dose combinations and simplification strategies may help. Further analyses are planned to : describe the development of resistance in this population compare rates of switching and suppression between adults and children.

15. Acknowledgements Sources of funding: Medical Research Council, ANRS, HIV Dutch Monitoring Foundation Steering commitee: Executive committee: Ian Weller (Chair, University College London), Dominique Costagliola (Vice-chair, FHDH), Bruno Ledergerber (Vice-chair, SHCS), Jesper Grarup (Head, Copenhagen Regional Co- ordinating Center), Genevieve Chene (Head, Bordeaux Regional Co-ordinating Centre). Contributing cohorts: Robert Zangerle (AHIVCOS), Giota Touloumi (AMACS), Josiane Warszawski (ANRS CO1 EPF), Laurence Meyer (ANRS CO2 SEROCO), François Dabis (ANRS CO3 AQUITAINE), Murielle Mary Krause (ANRS CO4 FHDH), Jade Ghosn (ANRS CO6 PRIMO), Catherine Leport (ANRS CO8 COPILOTE), Frank de Wolf (ATHENA), Peter Reiss (ATHENA), Maria Prins (CASCADE), Caroline Sabin (CHIC), Diana Gibb (CHIPS), Gerd Fätkenheuer (Cologne Bonn), Julia Del Amo (Co-RIS), Niels Obel (Danish HIV Cohort), Claire Thorne (ECS), Amanda Mocroft (EuroSIDA), Ole Kirk (EuroSIDA), Christoph Stephan (Frankfurt), Santiago Pérez-Hoyos (GEMES- Haemo), Dolors Carnicer (NENEXP), Andrea Antinori (ICC), Antonella d’Arminio Monforte (ICONA), Pier- Angelo Tovo (ITLR), Maurizio de Martino (ITLR), Bernd Salzberger (KOMPNET), José Ramos (Madrid Cohort), Manuel Battegay (MoCHIV), Patrick Francioli (SHCS), Cristina Mussini (Modena Cohort), Pat Tookey (NSHPC), Jordi Casabona (PISCIS), Jose M. Miró (PISCIS), Antonella Castagna (San Raffaele), Stephane de Wit (St. Pierre Cohort), Tessa Goetghebuer (Belgian Pediatric cohort, St Pierre)Carlo Torti (Italian Master Cohort), Ramon Teira (VACH),Myriam Garrido (VACH). European AIDS Treatment Group: Nikos Dedes. Project leaders and statistical analysis: Julia Bohlius, Vincent Bouteloup, Heiner Bucher,Alessandro Cozzi-Lepri, François Dabis, Antonella d’Arminio Monforte, Frank de Wolf, Maria Dorucci, Matthias Egger, Hansjakob Furrer, Ole Kirk, Olivier Lambotte, Charlotte Lewden, Rebecca Lodwick, Sophie Matheron, Laurence Meyer, Jose Miro, Amanda Mocroft, Roger Paredes,Andrew Phillips, Massimo Puoti, Joanne Reekie, Caroline Sabin, Colette Smit, Jonathan Sterne, Rodolphe Thiebaut, Claire Thorne, Linda Wittkop. PLATO II children analysis and writing committee Hannah Castro, Ali Judd, Di Gibb, Karina Butler, Rebecca Lodwick, Ard van Sighem, Jose Ramos, Josiane Warsawski, Claire Thorne, Joan Masip, Niels Obel, Dominique Costagliola, Pat Tookey, Céline Colin, Jesper Kjaer, Jesper Grarup, Genevieve Chene, Andrew Phillips on behalf of the PLATO II project team of COHERE Regional co-ordinating centers: Bordeaux RCC cohorts: Geneviève Chêne (Head), Céline Colin, Christine Schwimmer Copenhagen RCC cohorts: Michelle Ellefson, Jesper Grarup (Head), Jesper Kjaer, Maria Paulsen