Working Group 1:

1
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.

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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 lt3 yrs or wt lt10 kg NVP If age gt3 yrs or wt gt10 kg NVP or EFZ
3
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 gt25 kg
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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 childs age has
  implications for what drugs and formulations
  should be acquired by country to allow treatment
  of children.

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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).

6
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.

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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.

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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.

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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.

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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.

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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 doesnt have to list actual dose, it
  is CRITICAL to have dosing calculated and checked
  when developing table.

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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 ½ 30 mg d4T/3TC/NVP tab BID OR ½ 30 mg d4T/3TC tab BID plus ½ NVP tab BID ½ 30 mg d4T/3TC/NVP tab BID OR ½ 30 mg d4T/3TC tab BID plus ½ NVP tab BID
15-16.9 ½ 30 mg d4T/3TC/NVP tab BID OR ½ 30 mg d4T/3TC tab BID plus ½ NVP tab BID ½ 30 mg d4T/3TC/NVP tab BID OR ½ 30 mg d4T/3TC tab BID plus ½ NVP tab BID ½ 30 mg d4T/3TC/NVP tab BID OR ½ 30 mg d4T/3TC tab BID plus ½ NVP tab BID
17-19.9 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 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 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
20-24.9 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 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 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
25-29.9 1 30 mg d4T/3TC/NVP tab BID OR 1 30 mg d4T/3TC tab BID plus 1 NVP tab BID 1 30 mg d4T/3TC/NVP tab BID OR 1 30 mg d4T/3TC tab BID plus 1 NVP tab BID 1 30 mg d4T/3TC/NVP tab BID OR 1 30 mg d4T/3TC tab BID plus 1 NVP tab BID
30-34.9 1 30 mg d4T/3TC/NVP tab BID OR 1 30 mg d4T/3TC tab BID plus 1 NVP tab BID 1 30 mg d4T/3TC/NVP tab BID OR 1 30 mg d4T/3TC tab BID plus 1 NVP tab BID 1 30 mg d4T/3TC/NVP tab BID OR 1 30 mg d4T/3TC tab BID plus 1 NVP tab BID
35-40 1 40 mg d4T/3TC/NVP tab BID plus OR 1 40 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 1 40 mg d4T/3TC/NVP tab BID plus OR 1 40 mg d4T/3TC tab BID plus 1 NVP tab BID
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d4T/3TC/NVP 1st 2 weeks
Weight band (kg) d4T 3TC NVP
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
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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).

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Recommendations

• Principles for treatment of children
• Infants (lt12 kg) can and should be treated as
  well as older and heavier children.
• In order to treat infants lt12 kg, necessary to
  have following ARV
• AZT, ABC, 3TC
• NVP
• LPV/r
• Not recommended for use in lt12 kg are d4T liquid,
  ddI sachet, NFV powder.

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Recommendations

• Principles for treatment of children
• Children gt12 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

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Recommendations

• Development of simplified weight-range-based
  dosing table/card may provide a useful tool (see
  model)
• May need to be broken into lt12 kg tables and gt12
  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

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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 ½ 30 mg d4T/3TC/NVP tab BID OR ½ 30 mg d4T/3TC tab BID plus ½ NVP tab BID ½ 30 mg d4T/3TC/NVP tab BID OR ½ 30 mg d4T/3TC tab BID plus ½ NVP tab BID
15-16.9 ½ 30 mg d4T/3TC/NVP tab BID OR ½ 30 mg d4T/3TC tab BID plus ½ NVP tab BID ½ 30 mg d4T/3TC/NVP tab BID OR ½ 30 mg d4T/3TC tab BID plus ½ NVP tab BID ½ 30 mg d4T/3TC/NVP tab BID OR ½ 30 mg d4T/3TC tab BID plus ½ NVP tab BID
17-19.9 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 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 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
20-24.9 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 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 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
25-29.9 1 30 mg d4T/3TC/NVP tab BID OR 1 30 mg d4T/3TC tab BID plus 1 NVP tab BID 1 30 mg d4T/3TC/NVP tab BID OR 1 30 mg d4T/3TC tab BID plus 1 NVP tab BID 1 30 mg d4T/3TC/NVP tab BID OR 1 30 mg d4T/3TC tab BID plus 1 NVP tab BID
30-34.9 1 30 mg d4T/3TC/NVP tab BID OR 1 30 mg d4T/3TC tab BID plus 1 NVP tab BID 1 30 mg d4T/3TC/NVP tab BID OR 1 30 mg d4T/3TC tab BID plus 1 NVP tab BID 1 30 mg d4T/3TC/NVP tab BID OR 1 30 mg d4T/3TC tab BID plus 1 NVP tab BID
35-40 1 40 mg d4T/3TC/NVP tab BID plus OR 1 40 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 1 40 mg d4T/3TC/NVP tab BID plus OR 1 40 mg d4T/3TC tab BID plus 1 NVP tab BID
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d4T/3TC/NVP 1st 2 weeks
Weight band (kg) d4T 3TC NVP
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
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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

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GAPS

• Testing and diagnosis, particularly children lt18
  months.
• Adherence pull together existing tools to
  provide examples

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GAPS

• Role of non-physician personnel to provide
  treatment
• Promote
• Supervision mechanism
• Prevent anarchy