Gugulethu ART Programme Khayelitsha ART Programme McCord Hospital Red Cross Children’s Hospital

1. Gugulethu ART Programme Khayelitsha ART Programme McCord Hospital Red Cross Children’s Hospital Tygerberg Academic Hospital Harriet Shezi Clinic, Chris Hani Baragwanath Hospital Rahima Moosa Mother and Child Hospital Virologic failure and second-line ART in children in South Africa: IeDEA Southern Africa collaboration Mary-Ann Davies, Robin Wood, Gilles Van Cutsem, Janet Giddy, Brian Eley, Helena Rabie, Karl Technau, Harry Moultrie, Andrew Boulle

2. Background • No WHO definition of virologic failure in children • Recent US & European guidelines • Strict viral load criteria for switching • Poor access to viral load monitoring in resource-limited settings • Poor access to second-line formulations for children – rates of switching are low • E.g. 5.2% switched after 3 years in Côte d’Ivoire, despite virologic suppression in <50% of cohort • South African ART sites have access to viral load monitoring

3. Objectives • To describe probability of virologic failure and switch to second-line therapy. • To determine factors associated with virologic failure. • To investigate factors associated with switching to second-line in those who fail.

4. Methods 1 • Eligibility criteria for children • <16 years at initiation • ART-naive • ≥ 3 drugs • SA National Guidelines criteria for ART initiation

5. Methods • Outcomes • Virologic failure: 2 consecutive viral loads >10000 copies/ml after 24 weeks of treatment • Switch to second-line: Commencement of ≥2 new drugs with a class-switch in 3rd drug & preceding unsuppressed viral load • Analysis • Cox-proportional hazards models stratified by site to identify factors associated with failure and switch

6. Children included in analysis 6266 children from 7 cohorts 85 children excluded due to missing/inconsistent data at ART start 6181 children 697 children excluded Non-naïve (n=39) First regimen <3 drugs (n=64) First regimen unknown (n=594) 5484 children

7. Characteristics at ART start

8. SA national paediatric guidelines Pre-2004 Children < 6 months of age Children with tuberculosis

9. First-line regimens

10. Kaplan-Meier probability of virologic failure and switch 0.20 0.15 Probability 0.10 all switches to second line n=146 0.05 n=95 switch meeting failure definition 0.00 0 6 12 18 24 30 36 Time in months since ART start Number at risk (Virologic failure) 5484 (1) 4163 (126) 3174 (95) 2355 (43) 1706 (22) 1113 (12) 589 62/148 (42%) of children remaining in care for at least a year after failure are switched. virologic failure (>10000 copies/ml x2) n=310 Median time between failure and switch: 4.6 months (IQR: 1.5 – 8.5)

11. Two consecutive viral load measurements above cut-off value >400 >1000 >5000 >10000

12. Determinants of virologic failure (n=5484)

13. Determinants of switch (n=216)

14. Outcomes after switch (n=146) Loss to program at 1 year post switch: 11.3% (95%CI: 6.5 – 19.3) 55% virologically suppressed (95%CI: 40.9 – 68.6) LTF: 8.7% (4.6 – 16.2) TFO: 8.9% (4.7 – 16.7) Death: 2.9% (0.9 – 9.1)

15. Limitations • Generalisability • Missing data • Small number of failures and switches

16. Conclusions • Probability of virologic failure at 3 years = 11.4% (95%CI: 10.1 – 12.8). • Less than half of children remaining in care for at least a year after virologic failure initiate second-line. • Children on NNRTI-based regimens more likely to be switched.

17. Acknowledgements • All children and their caregivers from participating sites • Staff at participating sites • Staff at Universities of Cape Town and Bern Data Centers especially • Nicola Maxwell (data management) • Morna Cornell and Claire Graber(project management) • Funders: • National Institute of Allergy and Infectious Diseases • Eunice Kennedy Shriver National Institute of Child Health and Human Development