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 [email protected]

What to start with: older children

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

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

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

Choosing the 1st regimen

NRTI Backbone (2 NRTIs) +

PI

OR

NNRTI ?

Q1. Which backbone NRTIs?

0 -1 -2 -3 -4 0

PENTA 5 trial: ABC + 3TC

✓

Viral load Weight-for-age

1.8

1.6

1.4

1.2

1 0 -.2

-.4

-.6

.8

.6

.4

.2

0 1 2 3 Years from randomisation 4 ZDV/3TC ZDV/ABC 3TC/ABC 5 ZDV/3TC ZDV/ABC 3TC/ABC 1 2 3 Years from randomisation 4 Better viral load suppression Better growth AIDS 2007; 21: 947-955 5

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 1 st 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

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

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

ARROW trial Lancet 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

A nti R etroviral R esearch f O r W atoto

ARROW induction-maintenance randomisation Week 0 Week 36 Arm A 3TC ABC NVP/EFV Arm B Arm C

B=C 4 drugs

3TC ABC ZDV NVP/EFV

2NRTI/ NNRTI mainte nance B=A everyone on 3 drugs

3TC ABC ZDV NVP/EFV

3NRTI mainte nance

Change in CD4 % primary endpoint at 72/144 weeks

global p=0.31

0

p=0.0001

24 48

p=0.69

p=0.33

Early effect of induction on CD4% responses: not sustained past 36 weeks when all moved to 3-drugs

72 96 120 144 Weeks from randomisation 168 192 228 Arm A Arm B Arm C

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

Choosing the 1st regimen for >3 yr olds NRTI Backbone (2 NRTIs) +

PI

OR

NNRTI ?

Q2. PI

or

NNRTI ?

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

Time to Switch by Drug Class 1.00

0.75

0.50

PI NNRTI

0.25

p=0.64 0.00

0 24 48 72 96 120 144 168 192 216 Weeks from randomisation 240 264 288

At trial end On 1 st regimen Switched to 2 nd Off ART after 1 st regimen regimen PI 96 28 7 (N=131) 73% 21% 5% NNRTI (N=132) 92 32 6% 70% 24% 8

WHO 2013 recommended 1

st

line

WHO rationale for TDF 1

st

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 1 st line is intelligent in terms of sequencing, as AZT ✓ for 2 nd – K65R mutation increases HIV susceptibility to AZT line • BUT – limited TDF experience in young children • Concerns re: renal and bone toxicity +/- growth

Sequencing antiretroviral regimens

Individual vs programmatic approaches: •Programmatic approach is built on experience of individual responses •For 1 st and 2 nd line, pragmatic approach OK •For 3 rd 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.

Other considerations in choosing 1

st

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..

Would you give this girl efavirenz?!

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!

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

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

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

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

Xhosa initiation ceremony

Source: Brent Stirton

2013 WHO 2

nd

line for children / YP

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…

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

Thank you for your attention!