Regimen selection, sequencing, and adherence in youth with perinatally -acquired HIV

1. Regimen selection, sequencing, and adherence in youth with perinatally-acquired HIV Gareth Tudor-Williams Imperial College Healthcare NHS Trust St. Mary’s Hospital & Imperial College LONDON, UK g.tudor-williams@imperial.ac.uk

2. What to start with: older children

3. New Guidelines – general considerations • Guidelines not always evidence-based • public health oriented: simple, standardized, harmonised • Guiding principle is to enable treatment of a child before they develop severe disease • Over time, age-related CD4 thresholds for starting ARVs have risen • to avoid risk of severe disease • to avoid delays in starting treatment • to preserve long term immune function

4. Age and initial CD4 count predicts attainable adult CD4 level Prof Nigel Klein, Joanna Lewis et al in press, 2013

5. What to start with? • Long term treatment success requires • Convenience (once daily better than twice) • Safety and tolerability • Durable suppression • Intelligent sequencing of available combinations • Fixed Dose Combinations (FDC’s) for children • increasingly available through generic industry • Weight-band based dosing tables • minimise under- and over- dosing

6. Choosing the 1st regimen + PI NRTI Backbone (2 NRTIs) OR NNRTI ? Q1. Which backbone NRTIs?

7. PENTA 5 trial: ABC + 3TC✓ Weight-for-age Viral load Better viral load suppression Better growth AIDS 2007; 21: 947-955

8. PENTA 5 • Improved efficacy of 3TC/ABC over ZDV-containing regimens during 5 years of follow up • PENTA and S. African and now WHO 2013 guidelines recommend ABC/3TC as the NRTI backbone for 1st line (for YP <35kg) • know the HLA B*5701 in your population (individuals carrying this allele are at high risk of ABC hypersensitivity reaction, HSR) AIDS 2007; 21: 947-955

9. FDC for children of ABC + 3TC : Junior and Baby pills(CIPLA) (Recently become available in Uganda)

10. Would induction with 4 drugs, followed by maintenance with 3 drugs offer better virological / immunological outcomes?

11. ARROWtrialLancet 2013; 381: 1391-1403 • Randomised trial of monitoring practice and treatment strategies for the management of ART in African children • 1,200+ children; 5 year trial • Uganda and Zimbabwe Anti Retroviral Research fOr Watoto

12. ARROW induction-maintenance randomisation Week 0 Week 36 3TC SOC ABC Arm A NVP/EFV 2NRTI/ NNRTI mainte- nance 3TC ABC Arm B ZDV NVP/EFV INDUCTION 3NRTI mainte- nance 3TC ABC Arm C ZDV NVP/EFV B=A everyone on 3 drugs B=C 4 drugs

13. Change in CD4 %primary endpoint at 72/144 weeks global p=0.31 p=0.69 Early effect of induction on CD4% responses: not sustained past 36 weeks when all moved to 3-drugs p=0.33 p=0.0001

14. Conclusions • Early immunological / virological benefits of induction with 4 drugs were not sustained over the long-term • there was no evidence of early or late clinical benefit • early benefits were possibly more sustained in those with low CD4% - may be worth considering • What would have happened if they had continued with 4 drugs? • early CD4% and VL benefits might have been sustained? • but VL <400 c/ml in 83% of those on standard 2NRTI+NNRTI regimens after median 3.7 years on ART, so further improvements may be unlikely Lancet 2013; 381: 1391-1403

15. Choosing the 1st regimen for >3 yr olds + PI NRTI Backbone (2 NRTIs) OR NNRTI ? Q2. PI or NNRTI ?

16. PENPACT 1 (PENTA 9 / PACTG 390) Lancet Infect Dis 2011; 11: 273-283 Antiretroviral therapy initiation with a PI versus an NNRTI combination and switch at higher versus low viral load in HIV-infected children: an open randomised controlled phase 2/3 trial

17. Time to Switch by Drug Class 1.00 0.75 PI 0.50 Proportion of children not switched NNRTI 0.25 p=0.64 0.00 0 24 48 72 96 120 144 168 192 216 240 264 288 Weeks from randomisation

18. WHO 2013 recommended 1st line

19. WHO rationale for TDF 1st line • FDA and EMA have approved TDF for children > 2 yrs. • Harmonising treatment with adults may improve access • TDF is cheaper than ABC • Using non-thymidine NRTI analogues 1st line is intelligent in terms of sequencing, as AZT ✓ for 2nd line • K65R mutation increases HIV susceptibility to AZT • BUT – limited TDF experience in young children • Concerns re: renal and bone toxicity +/- growth

20. Sequencing antiretroviral regimens Individual vs programmatic approaches: • Programmatic approach is built on experience of individual responses • For 1st and 2nd line, pragmatic approach OK • For 3rd line and beyond, could argue need for individualised decision making… genotypic testing may identify drugs worth recycling, and avoid use of expensive options with little efficacy.

21. Other considerations in choosing1st line treatment • Assess likely adherence • recently relocated, new carer, new school system, etc • Choose initial regimen that has higher barrier to resistance, eg boosted PI rather than NNRTI • If you have the luxury to individualise treatment, consider personality of patient..

22. Would you give this girl efavirenz?!

23. Efavirenz doesn’t suit everyone! • Pre-existing psychopathology • Be aware of pharmaco-genomic issues • polymorphisms associated with slow metabolism • at risk of accumulating high plasma levels • therapeutic blood monitoring (TDM) useful • Consider sustained-release once daily NVP • but not a good choice if HBV or HCV co-infected!

25. Reasons for failure of therapy POOR ADHERENCE • DIMINISHED EFFICACY • Impaired absorption • Under-dosing • Difficult regimen • Drug interactions • PK-PD individual variation VIRAL RESISTANCE Transmitted resistance / pMTCT

26. Some challenges to adherence • Multiple co-infections (especially TB) needing pills +++ • Immune reconstitution inflammatory syndromes (IRIS) • Family disruption: • Multiple carers • Children as caretakers • Stigmatisation in school • Depression / Disclosure • Poverty • Transport

27. Promoting adherence • Increasing use of peer facilitators who talk about their personal successful experiences. • For example: • ’I place my ARVs in my school shoes , and make sure I swallow them before heading to school….’ From the Adolescent programme at Mulago Hospital in Kampala run by Dr Sabrina Bakeera-Kitaka

28. Adherence support • J of Int AIDS Soc, June 2013 Special Issue • Loads of useful ideas! • Allison Agwu & Lee Fairlie – review article • Lists 25 strategies to address non-adherence

29. Xhosa initiation ceremony Source: Brent Stirton

30. 2013 WHO 2nd line for children / YP

31. Summary • Strong support for WHO 2013 guidelines: very great thought has gone into intelligent sequencing of available options, and harmonising treatment across the age ranges • Nothing is set in stone! • Paediatric formulations in new classes, with minimal cross-resistance to previous regimens needed…

33. Acknowledgments • My colleagues in our multi-disciplinary ‘Family Clinic’ HIV team at St. Mary’s Hosp (London), especially Hermione Lyall, Caroline Foster, Sam Walters • My mentors: Cathy Wilfert, Phil Pizzo, Sam Katz, Hoosen Coovadia • Di Gibb, Andy Prendergast, Martina Penazzato, Helena Rabie, Sabrina Bakeera-Kitaka, Nigel Klein, Shaffiq Essajee, Philip Goulder, the PENTA family, and PENPACT team • The children and families under our care

34. Thank you for your attention!