Transcript Working Group 1: “Best Use” ARV for Children: Principles

Working Group 1: “Best Use” ARV for
Children: Principles
• Simplified and standardized guidelines for ARV
treatment of HIV-infected children are needed
to allow rapid scale-up of treatment in children
as well as adults.
• Recommendations are targeted at developing
countries (not mid-developed or developed
countries), taking into account realities in
terms of:
– Health care infrastructure
– Availability of human resources
– Socioeconomic context
– Currently available drug formulations
• Comments are based on use of existing WHO
pediatric ARV 1st and 2nd line regimen choices.
WHO Recommended First-line
ARV Regimen for Children
First-Line Regimen
Comment
d4T or ZDV
Plus
3TC
Plus
NVP or EFZ
NNRTI choice:
If age <3 yrs or wt <10 kg:
NVP
If age >3 yrs or wt >10 kg:
NVP or EFZ
WHO Recommended Second-Line ARV
Regimen for Treatment Failure in Children
First-Line Regimen
Second-Line Regimen
d4T or ZDV
ABC*
Plus
Plus
3TC
ddI
Plus
Plus
NVP or EFZ
Protease inhibitor:
LPV/r or NFV,
or SQV/r if wt >25 kg
Special Considerations for Pediatrics
• Drug PK varies by age:
– Younger children may need higher doses of
drug to achieve same levels as with lower
doses in older children.
– Yet PK in younger children not available for
some of the WHO recommended drugs (e.g.,
EFV under age 3 years and LPV/r under age 6
months), thus choice of drugs in 1st or 2nd
line regimens may differ depending on
child’s age – has implications for what drugs
and formulations should be acquired by
country to allow treatment of children.
Special Considerations for Pediatrics
• Dosing must be adjusted as child grows.
– Need to standardize to allow non-experts to
give.
– BSA-based dosing involves math
calculations and too complex.
– “Weight-band” dosing tables would be
optimal.
– Generally for most drugs in 1st and 2nd line,
in terms of weight band dosing, would prefer
over- rather than under-dosing, to avoid
development of resistance (exception might
be for drug with significant toxicity known to
be dose-associated, e.g., anemia and ZDV).
Special Considerations for Pediatrics
• Formulation issues:
– Not all tablets/capsules available in low
enough doses for children.
– However, liquid may need cold chain (e.g.,
d4T liquid) and be hard to store/administer.
– Splitting of adult tablets, while suboptimal,
may be only way to provide ART to ill child.
– Knowing there is even distribution of drug(s)
in tablet important if splitting tablets (some
FDC do not have even distribution of drugs
in tablets).
– Splitting tablets more than once (e.g., in half)
felt too inaccurate and not recommended.
Special Considerations for Pediatrics
• Formulation issues:
– Simplified table that has weight bands and
the amount of liquid, tablets or capsules (not
mg/kg or /m2 dosing instruction) is desirable
to allow projecting need for different
formulations for children and for ease
administration by non-experts (WG started to
develop, but need to verify dosing ranges
being provided).
– Principal would be to try to utilize the adult
FDC tablet formulations as much as
possible, restricting liquid formulations to
infants under 12 kg.
Special Considerations for Pediatrics
• Formulation issues:
– With use adult FDC preparations, be aware of
potential under- or over-dosing of individual
drug.
– For NVP, children in certain weight
categories would need FDC plus an
additional dose of NVP; NVP also has issue
of dose escalation.
• Implication: Must have ability to have
liquid or tablet formulation of NVP alone
available in addition to FDC.
Special Considerations for Pediatrics
• Formulation problems:
– Opening capsules and mixing in liquid or
food has been done to administer to
children.
– However, the stability of such preparations is
unknown.
• In vitro stability testing is needed of
solutions made from capsule powder.
– Additionally, bioequivalence testing in adults
of such preparations (either mixed in liquid
or food) is needed to assure drug is
absorbed and dose correct when
administered in this manner.
– Need for FDC in pediatric doses.
Special Considerations for Pediatrics
• Monitoring:
– Because of concerns related to dosing and
formulation problems and interim solutions
to split tablets or open capsules until better
preparations available:
• Will be critical to have operational
research done at sentinel sites to
determine viral and immune response,
• Additionally, important to have at least
some monitoring and tracking of clinical
(and CD4 if can) response at sites
providing treatment to children to assure
appropriate response is being seen.
“Weight Band” Dosing Charts
• Several examples exist, such as Columbia/CDC
chart and MSF chart.
• All difficult to read as have all drugs and
multiple formulations in one big table.
• Need to simplify but how best?
– Should there be a single table for each
combination (eg. a d4T/3TC/NVP chart, an
AZT/3TC/NVP chart), divided into first 2 weeks
and after escalation?
– Would use liquid preparation only when
absolutely necessary in young infants with
low weight, and move to use of FDC tablets as
soon as weight allows.
– While table doesn’t have to list actual dose, it
is CRITICAL to have dosing calculated and
checked when developing table.
d4T/3TC/NVP After Dose Escalation
Weight band (kg)
d4T
3TC
NVP
5-6.9
6 mL BID
2 mL BID
4 mL BID
7-9.9
15 mg cap BID
3 mL BID
6 mL BID
10-11.9
15 mg cap BID
4 mL BID
½ NVP tab BID
12-14.9
½ 30 mg d4T/3TC/NVP tab BID OR
½ 30 mg d4T/3TC tab BID plus ½ NVP tab BID
15-16.9
17-19.9
20-24.9
25-29.9
30-34.9
35-40
½ 40 mg d4T/3TC/NVP BID plus ½ NVP tab QD
OR ½ 40 mg d4T/3TC tab BID plus 1 NVP tab
in AM and ½ NVP tab in PM
1 30 mg d4T/3TC/NVP tab BID OR
1 30 mg d4T/3TC tab BID plus 1 NVP tab BID
1 40 mg d4T/3TC/NVP tab BID plus OR
1 40 mg d4T/3TC tab BID plus 1 NVP tab BID
d4T/3TC/NVP 1st 2 weeks
Weight band (kg)
5-6.9
7-9.9
10-11.9
12-14.9
15-16.9
17-19.9
20-24.9
25-29.9
30-34.9
35-40
d4T
3TC
NVP
Recommendations
• With current formulations we can
and should treat children with ARVs
today.
• Existing success stories examples.
– Romania, Botswana, Uganda, S Africa
• Development of further simplified
guidelines that would allow use of
non-physician personnel to provide
drugs (model tables).
Recommendations
• Principles for treatment of children
– Infants (<12 kg) can and should be
treated as well as older and heavier
children.
– In order to treat infants <12 kg,
necessary to have following ARV:
• AZT, ABC, 3TC
• NVP
• LPV/r
– Not recommended for use in <12 kg are
d4T liquid, ddI sachet, NFV powder.
Recommendations
• Principles for treatment of children
– Children >12 kg can be treated with
adult solid formulations by using weight
band-based dosing ranges (at least 5 kg
increments).
• FDC are preferred
• Dual FDC may be better than triple because
of potential under-dosing for some drugs
like NVP which then require supplementary
drug administration
• Tablets can be divided in half but not more
Recommendations
• Development of simplified weight-rangebased dosing table/card may provide a
useful tool (see model)
– May need to be broken into <12 kg tables and
>12 kg tables
– Separate table for each of recommended
combinations
– Front: Schema for dosing (for FDC provide
exact )
– Back: “Appropriate” dose range for drugs
within weight range
– Dose ranges need to be checked
d4T/3TC/NVP After Dose Escalation
Weight band (kg)
d4T
3TC
NVP
5-6.9
6 mL BID
2 mL BID
4 mL BID
7-9.9
15 mg cap BID
3 mL BID
6 mL BID
10-11.9
15 mg cap BID
4 mL BID
½ NVP tab BID
12-14.9
½ 30 mg d4T/3TC/NVP tab BID OR
½ 30 mg d4T/3TC tab BID plus ½ NVP tab BID
15-16.9
17-19.9
20-24.9
25-29.9
30-34.9
35-40
½ 40 mg d4T/3TC/NVP BID plus ½ NVP tab QD
OR ½ 40 mg d4T/3TC tab BID plus 1 NVP tab
in AM and ½ NVP tab in PM
1 30 mg d4T/3TC/NVP tab BID OR
1 30 mg d4T/3TC tab BID plus 1 NVP tab BID
1 40 mg d4T/3TC/NVP tab BID plus OR
1 40 mg d4T/3TC tab BID plus 1 NVP tab BID
d4T/3TC/NVP 1st 2 weeks
Weight band (kg)
5-6.9
7-9.9
10-11.9
12-14.9
15-16.9
17-19.9
20-24.9
25-29.9
30-34.9
35-40
d4T
3TC
NVP
Critical Needs
• Bioequivalence studies of generic
drug
• Need more PK data younger age
group and for certain drugs like NFV
• FDC that are scored to allow
breaking
• FDC that are in pediatric dosing
GAPS
• Testing and diagnosis, particularly
children <18 months.
• Adherence – pull together existing
tools to provide examples
GAPS
• Role of non-physician personnel to
provide treatment
– Promote
– Supervision mechanism
– “Prevent anarchy”