UK-CAB Jan05 Paediatric HIV Care UK-CAB - 28 Jan 2005 HIV i-Base

UK-CAB Jan05 www.i-Base.info

Paediatric HIV Care

UK-CAB - 28 Jan 2005

HIV i-Base


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%


Background 2In 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


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 cellsHIV-negative : normal = 35-40%


CD4 %

<12 mo 1-5 yrs 6-12 yrs

cat 1 >1500 >1000 >500no supp >25% >25% >25%

Cat 2 750-1500 500-1000 200-500mod 15-24% 15-24% 15-24%

Cat 3 <750 <500 <200severe <15% <15% <15%


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


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.


On HAARTChildren 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


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


Log10 HIV-1 RNA plotted against age with fitted line and 95% CI

Log 1

0 R

NA

cop

ies/

ml

Age in years

0 2 4 6 8 103

4

5

6


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/


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


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


ARVs used in childrenNRTIs

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

NNRTIsNevirapine (NVP) - suspensionEfavirenz (EFV) - syrup >3 years

PIsNelfinavir (NFV) - powder for oral suspensionLopinavir/r (LPV/r) - oral solution >2 yearsRitonavir (RTV) - oral solutionAmprenavir (APV) - oral solution >3 years

No liquid formulationIndinavir (IDV) - not from MerckSaquinavir (SQV)

EIsT-20 - 50 children in study but rarely used if other choices available


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


Dosing/ PK

Adult doses provide the reference point for paediatric doses Either body weight or body surface area (BSA) are used to adjust dosesFor 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


Calculating BSA

Body Surface Area (BSA) can be calculated with the following equation:

BSA (m2)=√ (Height (cm) X Weight (kg) /3600)


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 log10 copies/ml in only 3/12 (25%)

This study was stopped by it’s DSMB


When to start?PENTA Guidelines 2002

1 Always start ART ifClinical stage C or CD4 <15%

2 Consider ART ifClinical 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)


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?


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)?


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


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


Adherence

Particularly difficult issue in childrenDependent both on the child, and on the parent/carerDosing schedule - number and size of pillsTaste of liquid or powder formulationsAge of the child Fears regarding disclosure Awareness of their diagnosis

Adherence support• Age appropriate charts etc• Pill swallowing lessons• G-tubes


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?


Changing baseline PK

preterm full 1 m 1 y3 m 6 y Adult

body water

gastric acid

body fat

liver function

renal


0

5000

10000

15000

20000

25000

30000

35000

40000

0 2 4 6 8 10 12 14 16Time post dose (h)

Plasma Lopinavir (ng/ml)

Adult Paediatric

Lopinavir Concentrations(Data from Liverpool TDM Service)


0

5000

10000

15000

20000

25000

0 5 10 15 20 25Time post dose (h)

Plasma Nevirapine (ng/ml)

Adult Paediatric

Nevirapine Concentrations(Data from Liverpool TDM Service)


Reasons to consider TDM

• dose & plasma relationship is unpredictable

• concentration-effect relationship exists

• efficacy / toxicity not immediately obvious

• changing baseline PK

• practical dosing difficulties

Adults Kids

Y Y

Y Y

Y Y

N Y

N 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


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


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


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


Paediatric guidelines

• PENTA:

www.ctu.mrc.ac.uk/penta

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


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UK-CAB Jan05 Paediatric HIV Care UK-CAB - 28 Jan 2005 HIV i-Base