Draft WHO Pediatric ARV Guidelines Revision Summary

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Draft WHO Pediatric ARV Guidelines Revision
Summary
Lynne M. Mofenson, M.D. Pediatric, Adolescent and
Maternal AIDS Branch National Institute of Child
Health and Human Development National Institutes
of Health Department of Health and Human Services

• 10/23/05

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Considerations in Revision

• Stand-alone guidelines for children (in 2003,
  children incorporated into adult guidelines).
• Guidelines evidence-based but public health
  oriented simple, standardized.
• Any revisions should enable treatment of a child
  before they develop severe disease.
• To better identify risk of severe disease, may
  need to increase the number of age-related CD4
  risk thresholds.
• Use of new WHO pediatric staging to guide
  starting therapy, monitoring treatment.
• Need advocacy for early infant diagnosis
  advocacy for pediatric formulations simplified
  weight-band based dosing tables.

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When to Start Antiretroviral Therapy?

• In adults defer for as long as possible without
  clinical deterioration or compromising
  immunological response
• For children, considerations include that
• Highest mortality in children lt18 mo/o.
• Inability to diagnose infection lt18 mo/o is major
  problem for treatment.
• Need to start ARV in exposed child lt18 mo (need
  verify infection status at 18 mo).
• Response to ART
• ART availability for different ages
• Family, social, adherence aspects
• No randomized evidence

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Changes to Pediatric Guidelines When to Start

• Changed age-related CD4/TLC values from two to
  four age categories (based on HPPCMS data).
• Incorporated new ped HIV staging system into
  decisions
• Staging and recommendations for ART
• Stage 4 treat all regardless of lab
• Stage 3 treat all regardless of lab (except if
  child gt18 mos and CD4 available, use CD4 guided
  decision for TB, LIP, OHL, low plts)
• Stage 2 CD4 or TLC guided decision
• Stage 1 treat only if CD4 available for decision

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When to Start ARVs in Children
lt18 mos gt18 mos
Stage 4 CD4 All All
No CD4 All All
Stage 3 CD4 All All (except TB, OHL, LIP, thrombocytopenia, where do CD4 guided)
No CD4 All All
Stage 2 CD4 CD4 guided CD4 guided
No CD4 TLC guided TLC guided
Stage 1 CD4 CD4 guided CD4 guided
No CD4 Do not rx Do not rx
Stabilize any OI before initiate ARV
Pulmonary TB Eval CD4 (if avail)/clinical status
after several wks TB rx to decide if need ARV
and if so, when ARV start in relation to TB rx
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Draft WHO Age-Related CD4 and TLC values for
Antiretroviral Treatment Decisions in Children
Start ARV When CD4 or Count is Start ARV When CD4 or Count is Start ARV When CD4 or Count is Start ARV When CD4 or Count is Start ARV When CD4 or Count is Start ARV When CD4 or Count is Start ARV When CD4 or Count is
lt11 mo 1 yr - lt3 yr 1 yr - lt3 yr 3 yr - lt5 yr 3 yr - lt5 yr gt5 yr
CD4 lt25 lt20 lt20 lt15 lt15 lt15
CD4 count lt1,500 lt750 lt750 lt350 lt350 lt200
CD4 preferred in children lt5 years CD4 count preferred in children gt5 years. CD4 preferred in children lt5 years CD4 count preferred in children gt5 years. CD4 preferred in children lt5 years CD4 count preferred in children gt5 years. CD4 preferred in children lt5 years CD4 count preferred in children gt5 years. CD4 preferred in children lt5 years CD4 count preferred in children gt5 years. CD4 preferred in children lt5 years CD4 count preferred in children gt5 years. CD4 preferred in children lt5 years CD4 count preferred in children gt5 years.
If CD4 Assay Not Available, Start ARV When TLC Is If CD4 Assay Not Available, Start ARV When TLC Is If CD4 Assay Not Available, Start ARV When TLC Is If CD4 Assay Not Available, Start ARV When TLC Is If CD4 Assay Not Available, Start ARV When TLC Is If CD4 Assay Not Available, Start ARV When TLC Is If CD4 Assay Not Available, Start ARV When TLC Is
lt11 mos lt11 mos 1yr - lt3yr 3yr - lt5 yr gt5 yr gt5 yr
TLC lt4,000 lt4,000 lt3,000 lt2,500 lt1,500 lt1,500
ART should be started at these levels regardless
clinical stage
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12-Month Risk of Death By Age and TLC or CD4HIV
Pediatric Prognostic Marker Collaborative Study
lt1 yr 4,000
lt1 yr 25
1-3 yr 3,000
1-3 yr 20
3-5 yr 2,500
gt3 yr 15
gt5 yr 1,500
5
5
CD4
Total Lymphocyte Count
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Age-Related CD4 Absolute Count Associated With
5 Risk of Death Within 12 Months
1,500
750
350
200
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12-Month Mortality Risk, Selected CD4/Count and
TLC Age Thresholds HIV Pediatric Prognostic
Marker Collaborative Study (Dunn et al)
CD4lt25 (lt1yr), lt20 (1 to lt3 yrs), lt15 (3 to lt5
yrs), lt15 ( 5 yrs)
CD4lt1500 (lt1yr), lt750 (1 to lt3 yrs), lt350 (3 to
lt5 yrs), lt200 ( 5 yrs)
TLClt4000 (lt1yr), lt3000 (1 to lt3 yrs), lt2500 (3 to
lt5 yrs), lt1500 ( 5 yrs)
0
1
2
3
4
5
6
7
8
9
10
Age (years)
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Changes to Pediatric Guidelines What to Start

• ARV choice problem is lack pediatric formulations
  and lack of dose information for some ARV/ages.
• Excludes TFV 1st line therapy for children (no
  formulation, dose not defined, safety unclear) as
  opposed to adult recs.
• Add ABC to 1st line NRTIs as virologically
  superior to AZT/3TC (PENTA), and to begin to get
  away from d4T (did not want to completely change
  recs as countries just starting roll-out).
• Drugs
• Dual NRTI combination of AZT or d4T or 3TC or
  ABC (do not use AZT/d4T possible combos AZT/3TC,
  d4T/3TC, AZT/ABC, 3TC/ABC, d4T/ABC).
• plus NNRTI prefer NVP if lt3 yrs, EFV if gt3 yrs.
• 2nd line Continue 3TC re decreased viral
  fitness?
• Weight-band based dosing tables (underway).

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Changes to Pediatric Guidelines What to Start

• Issue of infant PMTCT exposure and resistance
• Resistance develops in mom pre- or during
  pregnancy, IP, PP while BF transmits to infant.
• Resistance developing infant during infant
  prophylaxis component.
• Important to note that not all failures of PMTCT
  are due to resistance (majority not resistant).
• Current rec Children with prior NVP or 3TC
  prophylaxis should be eligible for HAART,
  including NNRTI regimen and not denied access to
  life-saving therapy.
• Studies ongoing/to start in kids to address
  response to NNRTI therapy post SD NVP exposure.
• Since no new data and studies pending, no change
  recommended to current language.

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ARV REGIMENS for Pediatric Patients ARV REGIMENS for Pediatric Patients ARV REGIMENS for Pediatric Patients ARV REGIMENS for Pediatric Patients ARV REGIMENS for Pediatric Patients
1st Line ARV 1st Line ARV Considerations Considerations 2nd Line ARV
Dual NRTI (choose 2, except do not use AZT/d4T) Dual NRTI (choose 2, except do not use AZT/d4T) Dual NRTI (choose 2, except do not use AZT/d4T) Dual NRTI (choose 2, except do not use AZT/d4T) Dual NRTI (choose 2, except do not use AZT/d4T)
3TC or AZT d4T Minimal toxicity Anemia Lipodystrophy/lactic acidosis/ peripheral neuropathy Minimal toxicity Anemia Lipodystrophy/lactic acidosis/ peripheral neuropathy ddI ( 3TC?) ABC ( 3TC?) ddI ( 3TC?) ABC ( 3TC?)
or ABC Hypersensitivity reaction Hypersensitivity reaction AZT ( 3TC?) AZT ( 3TC?)
PLUS
NNRTI (choose 1, see age preference) NNRTI (choose 1, see age preference) NNRTI (choose 1, see age preference) NNRTI (choose 1, see age preference) NNRTI (choose 1, see age preference)
NVP or Prefer lt3 yr (lt10kg) Prefer lt3 yr (lt10kg) Prefer lt3 yr (lt10kg) LPV/r or SQV/r or SQV/NFV or NFV
EFV Prefer gt3 yr (gt10 kg) Prefer gt3 yr (gt10 kg) Prefer gt3 yr (gt10 kg) LPV/r or SQV/r or SQV/NFV or NFV
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Alternative ARV Choices for Pediatric Patients Alternative ARV Choices for Pediatric Patients Alternative ARV Choices for Pediatric Patients Alternative ARV Choices for Pediatric Patients Alternative ARV Choices for Pediatric Patients Alternative ARV Choices for Pediatric Patients
1st Line ARV 1st Line ARV Considerations Considerations Considerations 2nd Line ARV
3 NRTI Combo (choose 3 except do not use AZT/d4T) NRTI 3 NRTI Combo (choose 3 except do not use AZT/d4T) NRTI 3 NRTI Combo (choose 3 except do not use AZT/d4T) NRTI 3 NRTI Combo (choose 3 except do not use AZT/d4T) NRTI 3 NRTI Combo (choose 3 except do not use AZT/d4T) NRTI 3 NRTI Combo (choose 3 except do not use AZT/d4T) NRTI
3TC or AZT d4T Minimal toxicity Anemia Lipodystrophy/lactic acidosis/ peripheral neuropathy Minimal toxicity Anemia Lipodystrophy/lactic acidosis/ peripheral neuropathy ddI ( 3TC?) ddI ( 3TC?) ddI ( 3TC?)
or ABC Hypersensitivity reaction Hypersensitivity reaction
PLUS a PI PLUS a PI PLUS a PI PLUS a PI PLUS a PI PLUS a PI
LPV/r or SQV/r or SQV/NFV or NFV LPV/r or SQV/r or SQV/NFV or NFV
PLUS an NNRTI NVP or EFV PLUS an NNRTI NVP or EFV
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(No Transcript)
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Example of Weight-Based Dosing Table for Children
Including Pediatric and Adult Formulations
Weight (kg) Nevirapine syrup Nevirapine syrup Nevirapine tablets Nevirapine tablets
Weight (kg) Lead-in dose Weeks 1 2 syrup (10mg/ml) Full Dose syrup (10mg/ml) Lead-in dose Weeks 1 2 200mg tablets Full Dose 200mg tablets
5-6.9 2 4.5
7-9.9 3.5 7
10-11.9 4 8
12-14.9 5 10 ½ am only ½ am and pm
15-19.9 7 14 1 am or ½ am or pm 1 am and ½ pm
20-29.9 ½ am and pm 1 am and pm
30-34.9 1 am and pm
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Changes to Ped Guideline Monitoring Before and
While On ARVs

• Monitoring
• Primarily clinical-based.
• Importance of weight gain/maintenance in clinical
  evaluation.
• Encourage increased use CD4.
• Do not use TLC to monitor therapy (only for
  start).
• AZT baseline Hb suggested and recheck at 8
  weeks.
• Symptom-directed for other lab tests.

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Baseline and Monitoring Pediatric ARV Baseline and Monitoring Pediatric ARV
Baseline On ARV
Confirm dx N/A
Clinical stage Clinical stage
Readiness Adherence
Concom conditions/meds Concom conditions/meds
Wt, ht, develop Wt, Ht, growth, development
Nutritional status Nutritional status
CD4 (desirable not required) CD4 q 6-12 mos (or clinical indic)
Hb (esp if on AZT) Hb (WBC) 1-3 mos post start ARV, then Sx directed
Other lab Sx-directed, eg ALT, lipid, glucose
VL if available VL if indicated (to confirm CD4 drop?)
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Changes to Ped Guidelines Toxicity Management

• Improve description of toxicity in children.
• Outline temporal issues (early vs late).
• Immediate, life-threatening Stop all drugs.
  Once resolves, restart with substitute for
  offending drug.
• Staggered stopping if NNRTI?
• Non-life threatening
• Continue ARV if can, if mild or moderate.
• If severe, switch one offending drug (within
  class substitution usually) without stop.
• Late toxicity, such as lipodystrophy
• Management could change d4T to AZT.
• Include more details on management/algorithm?

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Changes to Ped Guidelines When to Switch for
Treatment Failure

• Important to check adherence before change.
• Must have adequate trial ARVs (eg, gt6 mos).
• Before change for growth failure, need assure
  adequate nutrition, treatment OIs (esp, TB).
• Algorithm development?
• Before change, must check adherence, nutrition,
  resolution TB/acute OI.
• Use new clinical staging for decisions?
• New or recurrent Stage 3 or 4 change.
• New or recurrent Stage 3 (selected conditions?)
  consider change?
• If use CD4 criteria, need repeat value before
  change (also clinical status important in
  decision).

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Changes to Ped Guidelines When to Switch

• When Switch for Treatment Failure
• Clinical criteria (if keep selected selected
  clinical criteria vs use of pediatric clinical
  staging)
• Lack/decline in growth
• Weight most important
• Must be sure unexplained (eg, in presence of
  adequate nutrition, treated TB, etc).
• Loss developmental milestones/ encephalopathy
• New or recurrent OI
• Must differentiate from IRS

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Changes to Ped Guidelines When to Switch

• When Switch for Treatment Failure
• CD4 criteria
• If only CD4 and no symptoms, may decide not to
  change.
• Viral load monitoring may be useful in this
  situation (confirm significance).
• If after reasonable trial of therapy (eg, after 6
  months of therapy), switch if CD4 not above or if
  declines to age-related threshold for initiation
  of therapy (considering clinical status).
• Include a change from peak? Does baseline value
  matter?
• Absence of any concurrent conditions that can be
  associated with lowered CD4.

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Potential Proposal to Use Clinical Staging to
Decide on Switch Due to Treatment Failure
Clinical stage Considerations
1 No switch
2 new or recurrent Consider adherence Monitor closely clinical
3 new or recurrent Check adherence Rx/manage coinfection/OI (eg, TB ) Nutritional issues if growth criteria Consider regimen switch
4 new or recurrent Check adherence Rx/manage coinfection/OI (eg, TB) Nutritional issues if growth criteria Switch regimen
TB may not indicate treatment failure
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Changes to Ped Guidelines TB and ARV

• TB and ARV
• Drug interactions especially problem in kids due
  to lack pediatric ARV formulation/drug dosing
  younger kids, so not many choices.
• Need emphasize case detection (child with TB may
  reflect TB in household not necessarily immune
  suppression).
• TB diagnosis difficulty in kids, most often
  empiric therapy issue (dx TB if respond to TB
  treatment).
• All kids with pulmonary TB should be CONSIDERED
  for ARV (stage III).
• CD4 thresholds used to determine overall need for
  start ARV in child with pulmonary TB are as per
  when to start thresholds.

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Changes to Ped Guidelines TB and ARV

• TB and ARV
• Importance of clinical response to TB rx in
  determining when ARV start in relation to TB rx
  (or whether to start ARV if no CD4 available).
• When start ARV if pulmonary TB in child?
• Stabilize TB before make decisions ARV (response
  first few weeks of TB rx)
• If respond well to TB rx, defer ARV until
  complete TB rx.
• If not respond after initial TB rx, start ARV.
• Where does CD4 fit in this determination? Adult
  group will have CD4 gradation to determine when
  to start ARV in pt with TB (lt200 start ARV 2wk-2
  mos of TB rx 200-350 defer till complete TB rx).
  Should we have this for children and, if so,
  what thresholds?

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Changes to Ped Guidelines TB and ARV

• TB and ARV
• What ARV to start (or to change if on 1st line)
  if on rifampin
• If lt3 yrs
• Triple NRTI (eg, AZT/3TC/ABC) (TFV role?)
• vs
• NVP-based ARV
• Adult group may say continue NVP-based therapy if
  no other options are available.
• If gt3 yrs
• EFV-based (no dose increase)

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Changes to Ped Guidelines TB and ARV

• TB and ARV
• If on 2nd line therapy
• If have failed NNRTI, then is now receiving
  boosted PI, which is contraindicated with
  rifampin.
• Stop PI and use triple NRTI including TFV if
  age-appropriate (dose/formulation issues cant
  give with concurrent ddI).
• Adult group says could still use boosted PI
  (LPV/r or SQV/r SQV/NFV?) but with increased
  monitoring (LFT) who concurrent boosted PI and
  rifampin rx.
• Adult group to advocate for availability of
  rifabutin (then can give boosted PI or NNRTI).

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Changes to Ped Guidelines Adherence

• Adherence
• Two types problems
• Program level (cost, formulations, supply)
• Reduce cost/free drug
• Reliable supply forecasting needs
• Pediatric formulation needs
• Individual level
• Discuss challenges in children, how to maximize
• Education, pro-active approach
• Reduce pill burden
• Disclosure
• DOT/outreach/community
• Family focused care

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Other suggested changes to Ped Guidelines

• Treatment interruptions
• Not enough information to make recommendations on
  this
• Adolescent section
• Discuss EFV issues in adolescent girls,
  contraception
• Deal with transition to adult care
• Salvage
• Not enough info ped drugs, needs
  individualization
• HBV/HCV coinfection
• Will be some discussion in adult guidelines
  should ped cover as well?