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. [email protected] 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

[email protected]

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 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
Choosing the 1st regimen

+

PI

NRTI Backbone

(2 NRTIs)

OR

NNRTI ?

Q1. Which backbone NRTIs?

penta 5 trial abc 3tc
PENTA 5 trial: ABC + 3TC✓

Weight-for-age

Viral load

Better viral load suppression

Better growth

AIDS 2007; 21: 947-955

penta 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 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

slide9

FDC for children of ABC + 3TC :

Junior and Baby pills(CIPLA)

(Recently become available in Uganda)

slide10

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

arrow trial lancet 2013 381 1391 1403
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

arrow induction maintenance randomisation
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

change in cd4 primary endpoint at 72 144 weeks
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

conclusions
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
Choosing the 1st regimen for >3 yr olds

+

PI

NRTI Backbone

(2 NRTIs)

OR

NNRTI ?

Q2. PI or NNRTI ?

penpact 1 penta 9 pactg 390

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
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

who rationale for tdf 1 st 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
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 choosing 1 st line treatment
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..
efavirenz doesn t suit everyone
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
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
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
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
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
Xhosa initiation ceremony

Source: Brent Stirton

summary
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
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
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