Regimen selection sequencing and adherence in youth with perinatally acquired hiv
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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. What to start with: older children.

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Regimen selection sequencing and adherence in youth with perinatally acquired hiv
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


What to start with older children
What to start with: older children


New guidelines general considerations
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
Age and initial CD4 count predicts attainable adult CD4 level

Prof Nigel Klein,

Joanna Lewis et al

in press, 2013


What to start with
What to start levelwith?

  • 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
Choosing the 1st regimen level

+

PI

NRTI Backbone

(2 NRTIs)

OR

NNRTI ?

Q1. Which backbone NRTIs?


Penta 5 trial abc 3tc
PENTA 5 trial: ABC + 3TC level✓

Weight-for-age

Viral load

Better viral load suppression

Better growth

AIDS 2007; 21: 947-955


Penta 5
PENTA 5 level

  • 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


Regimen selection sequencing and adherence in youth with perinatally acquired hiv

FDC for children of ABC + 3TC : level

Junior and Baby pills(CIPLA)

(Recently become available in Uganda)


Regimen selection sequencing and adherence in youth with perinatally acquired hiv

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


Arrow trial lancet 2013 381 1391 1403
ARROW drugs offer better virological / immunological outcomes?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
ARROW induction-maintenance randomisation drugs offer better virological / immunological outcomes?

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


Change in cd4 primary endpoint at 72 144 weeks
Change in CD4 % drugs offer better virological / immunological outcomes?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


Conclusions
Conclusions drugs offer better virological / immunological outcomes?

  • 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
Choosing the 1st regimen for >3 drugs offer better virological / immunological outcomes?yr olds

+

PI

NRTI Backbone

(2 NRTIs)

OR

NNRTI ?

Q2. PI or NNRTI ?


Penpact 1 penta 9 pactg 390

PENPACT 1 drugs offer better virological / immunological outcomes?(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
Time to Switch by Drug Class drugs offer better virological / immunological outcomes?

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


Who 2013 recommended 1 st line
WHO 2013 recommended 1 drugs offer better virological / immunological outcomes?st line


Who rationale for tdf 1 st line
WHO rationale for TDF 1 drugs offer better virological / immunological outcomes?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 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
Sequencing antiretroviral regimens drugs offer better virological / immunological outcomes?

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 choosing 1 st line treatment
Other considerations in choosing drugs offer better virological / immunological outcomes?1st 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..


Regimen selection sequencing and adherence in youth with perinatally acquired hiv

Would you give this girl drugs offer better virological / immunological outcomes?efavirenz?!


Efavirenz doesn t suit everyone
Efavirenz doesn drugs offer better virological / immunological outcomes?’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
Reasons for failure of therapy drugs offer better virological / immunological outcomes?

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
Some challenges to adherence drugs offer better virological / immunological outcomes?

  • 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
Promoting adherence drugs offer better virological / immunological outcomes?

  • 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
Adherence support drugs offer better virological / immunological outcomes?

  • 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
Xhosa initiation ceremony drugs offer better virological / immunological outcomes?

Source: Brent Stirton


2013 who 2 nd line for children yp
2013 WHO 2 drugs offer better virological / immunological outcomes?nd line for children / YP


Summary
Summary drugs offer better virological / immunological outcomes?

  • 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
Acknowledgments drugs offer better virological / immunological outcomes?

  • 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
Thank you for your attention! drugs offer better virological / immunological outcomes?