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Draft WHO Pediatric ARV Guidelines Revision Summary

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. Considerations in Revision.

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Draft WHO Pediatric ARV Guidelines Revision Summary

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  1. 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

  2. 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.

  3. 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 <18 mo/o. • Inability to diagnose infection <18 mo/o is major problem for treatment. • Need to start ARV in exposed child <18 mo (need verify infection status at 18 mo). • Response to ART • ART availability for different ages • Family, social, adherence aspects • No randomized evidence

  4. 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 >18 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

  5. When to Start ARVs in Children * 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

  6. Draft WHO Age-Related CD4 and TLC values for Antiretroviral Treatment Decisions in Children +ART should be started at these levels regardless clinical stage

  7. 12-Month Risk of Death By Age and TLC or CD4%HIV Pediatric Prognostic Marker Collaborative Study <1 yr 4,000 <1 yr 25% 1-3 yr 3,000 1-3 yr 20% 3-5 yr 2,500 >3 yr 15% >5 yr 1,500 5% 5% CD4% Total Lymphocyte Count

  8. Age (yrs) 5% Risk of Death CD4% CD4 count 0.5 36 1748 1 23 1162 1.5 18 808 2 16 572 2.5 14 409 3 13 294 4 11 153 5 9 143 6 8 134 7 8 125 8 7 117 9 7 110 10 6 103 Age-Related CD4 Absolute Count Associated With 5% Risk of Death Within 12 Months 1,500 750 350 200

  9. 30 25 20 15 Probability of death (%) 10 5 0 12-Month Mortality Risk, Selected CD4%/Count and TLC Age Thresholds HIV Pediatric Prognostic Marker Collaborative Study (Dunn et al) CD4%<25 (<1yr), <20% (1 to <3 yrs), <15% (3 to <5 yrs), <15% (≥5 yrs) CD4<1500 (<1yr), <750 (1 to <3 yrs), <350 (3 to <5 yrs), <200 (≥5 yrs) TLC<4000 (<1yr), <3000 (1 to <3 yrs),<2500 (3 to <5 yrs), <1500 (≥5 yrs) 0 1 2 3 4 5 6 7 8 9 10 Age (years)

  10. 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 <3 yrs, EFV if >3 yrs. • 2nd line: Continue 3TC re: decreased viral fitness? • Weight-band based dosing tables (underway).

  11. 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.

  12. Example of Weight-Based Dosing Table for Children Including Pediatric and Adult Formulations

  13. 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.

  14. 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?

  15. Changes to Ped Guidelines: When to Switch for Treatment Failure • Important to check adherence before change. • Must have adequate trial ARVs (eg, >6 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).

  16. 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

  17. 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.

  18. Potential Proposal to Use Clinical Staging to Decide on Switch Due to Treatment Failure # TB may not indicate treatment failure

  19. 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.

  20. 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 (<200 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?

  21. 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 <3 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 >3 yrs: • EFV-based (no dose increase)

  22. 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; can’t 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).

  23. 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

  24. 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?

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