UK-CAB Jan05 Paediatric HIV Care UK-CAB - 28 Jan 2005 HIV i-Base.
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Transcript of 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
UK-CAB Jan05 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%
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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
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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%
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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%
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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 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
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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
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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
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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/
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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
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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
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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
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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
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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
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Calculating BSA
Body Surface Area (BSA) can be calculated with the following equation:
BSA (m2)=√ (Height (cm) X Weight (kg) /3600)
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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
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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)
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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
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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 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
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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
preterm full 1 m 1 y3 m 6 y Adult
body water
gastric acid
body fat
liver function
renal
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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)
UK-CAB Jan05 www.i-Base.info
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)
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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
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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
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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
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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
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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
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Paediatric guidelines
• PENTA:
www.ctu.mrc.ac.uk/penta
www.ctu.mrc.ac.uk/penta/guidelines.htm
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http://www.i-base.info
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