UK-CAB Jan05

Paediatric HIV Care

UK-CAB - 28 Jan 2005

HIV i-Base www.i-Base.info

Background 1

• Three years after the first descriptions (in 1981) of adult AIDS cases, similar disease characteristics were reported in children • Early 80s – most HIV+ children infected by blood transfusion (greatly reduced following the introduction of HIV specific antibody tests in 1985) • Since the early 90s the number of vertically infected children increased - approx 1200 in UK • Approx 950 HIV+ children in UK now • With ARV treatment transmission is now <1% UK-CAB Jan05 www.i-Base.info

Background 2

In general: • HIV progresses more rapidly in children than in adults • Very high CD4 compared to adults (CD4%)  More rapid decrease of CD4 cells  Higher viral load at same CD4 count  Impaired growth UK-CAB Jan05 www.i-Base.info

CD4 %

Lymphocytes are white blood cells (B cells and T cells) 2 main types of T-cells: T-4 cells and T-8 cells Absolute CD4 count used to be the product of Total Lymphocytes and percentage that are CD4 (pre 1996, now CD4 cells are counted) The CD4% is the % of T-cells that are CD4 cells HIV-negative : normal = 35-40% UK-CAB Jan05 www.i-Base.info

CD4 %

cat 1 no supp Cat 2 mod <12 mo >1500 >25% 750-1500 15-24% 1-5 yrs >1000 >25% 500-1000 15-24% 6-12 yrs >500 >25% 200-500 15-24% Cat 3 severe <750 <15% <500 <15% <200 <15% UK-CAB Jan05 www.i-Base.info

CD4 %

CD4% is useful in adult care - less variability but does not add any information to prediction of risk of illness CD4% is ESSENTIAL in paediatric care

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However

With effect ARV treatment: • mortality rates declining from 5.4% in 1995 to 1% in 1998.

Children have an increased ability to recover from the damage caused by HIV.

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On HAART

Children experience significant CD4 increases – 320 to 650 cells in the first year of treatment (vs adults 100 to 250) - but this dependent on age and limitations of CD4 count • more naïve cells than adults • Importance of age - ie the younger you are, the more likely to get higher numbers of CD4 cells • CD4 can increase to normal or near normal levels even with detectable viral load Some ‘miraculous’ results, though not universally successful UK-CAB Jan05 www.i-Base.info

How are children different?

Different immunology • Immature immune system • Functioning thymus • Higher level and more variation of CD4 cells (this declines with age) Different pattern of HIV RNA • Decline of HIV viral load up to 5 years Different metabolism • Different absorption rates to adults • Different elimination rates • Metabolism changing at different ages UK-CAB Jan05 www.i-Base.info

Log

10

HIV-1 RNA plotted against age with fitted line and 95% CI

6 5 4 UK-CAB Jan05 3 0 2 4 6 8 Age in years www.i-Base.info

10

Children’s clinical trials

Many questions about treatment for HIV can be answered in adult trials and so it is unnecessary to repeat all trials in children. This has been controversial in the past. (viral load etc) PENTA

(Paediatric European Network for Treatment of AIDS)

http://www.ctu.mrc.ac.uk/penta/ PACTG

(Paediatric AIDS Clinical Trials Group)

http://pactg.s-3.com/ UK-CAB Jan05 www.i-Base.info

Clinical trials in children

• Issues – Tolerability and toxicity – When to treat – Choice of endpoints for efficacy • Problems – Limited numbers of children (almost all trials underpowered for age) – Limited anti-HIV drugs with paediatric formulations – Need to study pharmacokinetics of agents in different age groups UK-CAB Jan05 www.i-Base.info

Clinical Trials in Children

• Focus on questions specific to children • Address issues of pharmacokinetics, toxicity and tolerability • Multinational collaborations (legal, cultural) • Address several questions at a time • Different ethical issues (ie recent GSK report in NYC) • Close collaboration with adults UK-CAB Jan05 www.i-Base.info

ARVs used in children

NRTIs Abacavir (ABC) - oral solution Didanosine (ddI) - powder for oral solution Lamivudine (3TC) - oral solution Stavudine (d4T) - oral solution Zidovudine (ZDV, AZT) - oral solution Tenofovir - crushed tablets FTC NNRTIs Nevirapine (NVP) - suspension Efavirenz (EFV) - syrup >3 years PIs Nelfinavir (NFV) - powder for oral suspension Lopinavir/r (LPV/r) - oral solution >2 years Ritonavir (RTV) - oral solution Amprenavir (APV) - oral solution >3 years No liquid formulation Indinavir (IDV) - not from Merck Saquinavir (SQV) EIs T-20 - 50 children in study but rarely used if other choices available UK-CAB Jan05 www.i-Base.info

Dosing

• Paediatric dosing is based on limited data • It is liable to change as new information becomes available • Use in clinical practice can often differ from doses recommended in licensed SPC UK-CAB Jan05 www.i-Base.info

Dosing/ PK

 Adult doses provide the reference point for paediatric doses  Either body weight or body surface area (BSA) are used to adjust doses  For a ‘typical’ 5 year old a BSA calculated dose could be over 50% greater than one adjusted by weight For AZT this 5 year old would receive a dose of 80mg with a mg/kg adjustment vs a dose of 140mg with a BSA adjustment UK-CAB Jan05 www.i-Base.info

Calculating BSA

Body Surface Area (BSA) can be calculated with the following equation: BSA (m2)=√ (Height (cm) X Weight (kg) /3600) UK-CAB Jan05 www.i-Base.info

Penta 7 Study

Design

: A multicentre phase I/II non comparative study of ddI, D4T, NFV in infants < 12 weeks of age, without AIDS.

Objectives

:To describe the tolerability, toxicity & antiviral activity of early treatment Nelfinavir started at 120 mg/kg/day Increased to 150/kg/day (this represents 5 times the equivalent adult dose!) AT 24 weeks <50 log 10 copies/ml in only 3/12 (25%) This study was stopped by it’s DSMB UK-CAB Jan05 www.i-Base.info

When to start?

PENTA Guidelines 2002

1 Always start ART if Clinical stage C or CD4 <15% 2 Consider ART if Clinical stage B or CD 4 <20% or High VL (>6 log if age < 1 year, >5 log if age over 1 year

)

3 Defer ART if Stage N or A disease, and CD4 > 20 %, and, Low VL (<6 log if age < 1year, and <5 log if age over 1 year) UK-CAB Jan05 www.i-Base.info

Issues to consider when starting therapy in children

• Parents wishes • Likelihood of good long term adherence • What formulations could this child take?

• What PK data are available?

• What drugs are other family members on?

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Starting therapy early

• Advantages

    Allow normal development of the immune system Positive effect on long-term natural history (especially for babies born to treated mothers) Possibility to clear infection (babies)?

Reset set point after primary infection, if stop • Disadvantages  Some children don’t need HAART for many years  Long term effects of ART on QoL    Short and long term toxicity Getting the right dose!!!

Possibility to develop resistance (inadequate PK, adherence) and reduce future HAART options  Loose HIV specific immune responses (babies)?

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Early therapy for infants

• If decide to start early: – Resistance testing at baseline if mother on ART – Choose regimen based on tolerability and PK – Support for adherence – Think about management for toxicity, failure, success • If decide to defer: – Monitor clinical, growth, CD4 and HIV RNA – Base decision on rate of change as well as absolutes UK-CAB Jan05 www.i-Base.info

Practical matters

• • • • • •

food intake requirements sleep requirements dosage issues with teaspoons / liquids formulation of medications children vomit more easily accidental overdose

• • • • •

Pill/liquid burden Ease of administration With/without food Number of times per day Creative use of drug-drug interactions

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Adherence

    

Particularly difficult issue in children

 Dependent both on the child, and on the parent/carer Dosing schedule - number and size of pills Taste of liquid or powder formulations Age of the child Fears regarding disclosure Awareness of their diagnosis

Adherence support

• • • Age appropriate charts etc Pill swallowing lessons G-tubes UK-CAB Jan05 www.i-Base.info

Pharmacokinetics

Definition: ‘The action of drugs in the body, including the processes of absorption, transformation, distribution to tissues, duration of action and elimination.

• Age dependent • Depends on surface area • Variability • NNRTI’s and PI’s cleared more rapidly in children • Dosing in puberty?

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Changing baseline PK

200 150 100 50 0

preterm

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full 1 m 3 m

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1 y 6 y

80

body water

60

liver function renal gastric acid body fat

40 20 0

Adult

quarter 1 2 3 4 5 6 7 8 9 10 11 12 13 14

40000

Lopinavir Concentrations

(Data from Liverpool TDM Service)

Adult Paediatric 35000 30000 25000 20000 15000 10000 5000 0 0 2 4 6 8 10

Time post dose (h)

12 14 16 UK-CAB Jan05 www.i-Base.info

25000

Nevirapine Concentrations

(Data from Liverpool TDM Service)

Adult Paediatric 20000 15000 10000 5000 0 0 UK-CAB Jan05 5 10 15

Time post dose (h)

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20 25

Reasons to consider TDM

•

dose & plasma relationship is unpredictable Adults Kids Y Y

•

concentration-effect relationship exists

•

efficacy / toxicity not immediately obvious

•

changing baseline PK

•

practical dosing difficulties

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Y Y N N Y Y Y Y

Limitations of TDM

• • • • • • • Highly dependent on information on time of dose Only reflection of situation before visit) Only one drug in the combination Difficulty taking blood PIs are highly bound to protein; protein levels may vary within and between patients Compartments - only measuring blood plasma Optimal frequency of sampling unknown – example: wk 4, 8, 12, then every 12 weeks UK-CAB Jan05 www.i-Base.info

Models of care

St Mary’s family clinic, London

• Established in 1993 as family HIV clinic • Families can be seen in a single hospital visit • Inpatient and outpatient • Holistic model - multidisciplinary team including: psychologist, physiotherapist, dietician, specialist health visitor, social worker as well as HIV paediatricians, adult clinician, obstetrician. pharmacist and clinical nurse specialist • 85% clinic population from sub-saharan Africa UK-CAB Jan05 www.i-Base.info

Sophia Children’s Hospital, University of Rotterdam

• Created in 1997 by group of Dutch paediatricians • Multidisciplinary study group • Over 40 kids enrolled in a protocol using IDV/ZDV/3TC - all comers ‘Research questions should only be raised when they serve to improve the quality of life with children’ Ronald de Groot UK-CAB Jan05 www.i-Base.info

Issues for advocates and parents

• Individuality of any situation • Relationship to research from adult care • New formulations for pipeline and existing drugs • Ethical issues, especially trials • Ethical issues relating to PEG tubes • Implications of long-term treatment and toxicity UK-CAB Jan05 www.i-Base.info

Paediatric guidelines

• PENTA: www.ctu.mrc.ac.uk/penta

www.ctu.mrc.ac.uk/penta/guidelines.htm

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