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

Gareth Tudor-Williams

Imperial College Healthcare NHS TrustSt. Mary’s Hospital

&Imperial CollegeLONDON, UK g.tudor-williams@imperial.ac.uk

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?

PENTA 5 trial: ABC + 3TC ✓Viral load Weight-for-age

Better viral load suppression

Better growth

AIDS 2007; 21: 947-955

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

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 trialLancet 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

ARROW induction-maintenance randomisation

B=C4 drugs

B=Aeveryone on 3 drugs

3NRTImainte-nance

2NRTI/NNRTImainte-nance

IND

UCT

ION

SOC

Week 0 Week 363TCABCNVP/EFV

3TCABCNVP/EFVZDV

3TCABCNVP/EFVZDV

Arm A

Arm B

Arm C

05

1015

2025

0 24 48 72 96 120 144 168 192 228Weeks from randomisation

Arm A Arm B Arm C

(95%

CI)

Mea

n ch

ange

from

rand

omis

atio

n

Mean change in CD4%

p=0.33

p=0.69

p=0.0001

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

global p=0.31

Change in CD4 %primary endpoint at 72/144 weeks

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)

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

Lancet Infect Dis 2011; 11: 273-283

Time to Switch by Drug Class

At trial end PI (N=131)

NNRTI (N=132)

On 1st regimen 96 73% 92 70%Switched to 2nd regimenOff ART after 1st regimen

2821%75%

32 24% 86%

0.00

0.25

0.50

0.75

1.00

Pro

porti

on o

f chi

ldre

n no

t sw

itche

d

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

Weeks from randomisation

p=0.64

PINNRTI

WHO 2013 recommended 1st line

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

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.

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..

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

VIRAL RESISTANCE

POOR ADHERENCE DIMINISHED EFFICACY• Impaired absorption• Under-dosing• Difficult regimen• Drug interactions• PK-PD individual variation

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 adherenceIncreasing 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 Kampalarun 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 2nd 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!