1. Draft WHO Pediatric ARV Guidelines Revision Summary 10/23/05 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

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 <18 mos>18 mos Stage 4*CD4All No CD4All Stage 3*CD4AllAll (except TB**, OHL, LIP, thrombocytopenia, where do CD4 guided) No CD4AllAll** Stage 2CD4CD4 guided No CD4TLC guided Stage 1CD4CD4 guided No CD4Do 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

6. Draft WHO Age-Related CD4 and TLC values for Antiretroviral Treatment Decisions in Children Start ARV When CD4% or Count is + : <11 mo1 yr - <3 yr3 yr - <5 yr>5 yr CD4%* <25%<20%<15% CD4 count* <1,500<750<350<200 *CD4% preferred in children 5 years. If CD4 Assay Not Available, Start ARV When TLC Is + : <11 mos1yr - <3yr3yr - <5 yr>5 yr TLC <4,000<3,000<2,500<1,500 + 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 3-5 yr 2,500 1-3 yr 3,000 <1 yr 4,000 >5 yr 1,500 5% Total Lymphocyte Count CD4% 5% <1 yr 25% 1-3 yr 20% >3 yr 15%

8. Age (yrs)5% Risk of Death CD4%CD4 count 0.5361748 1231162 1.518808 216572 2.514409 313294 411153 59143 68134 78125 87117 97110 106103 1,500 750 350 200 Age-Related CD4 Absolute Count Associated With 5% Risk of Death Within 12 Months

9. 012345678910 Age (years) 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) TLC<4000 (<1yr), <3000 (1 to <3 yrs), <2500 (3 to <5 yrs), <1500 (≥ 5 yrs) CD4<1500 (<1yr), <750 (1 to <3 yrs), <350 (3 to <5 yrs), <200 (≥ 5 yrs)

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 1 st line therapy for children (no formulation, dose not defined, safety unclear) as opposed to adult recs. Add ABC to 1 st 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. 2 nd 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. ARV REGIMENS for Pediatric Patients 1 st Line ARVConsiderations2 nd Line ARV Dual NRTI (choose 2, except do not use AZT/d4T) 3TC or AZT [d4T] Minimal toxicity Anemia Lipodystrophy/lactic acidosis/ peripheral neuropathy ddI (+ 3TC?) ABC (+ 3TC?) or ABC Hypersensitivity reactionAZT (+ 3TC?) PLUS NNRTI (choose 1, see age preference) NVP or Prefer <3 yr (<10kg) LPV/r or SQV/r or SQV/NFV or NFV EFVPrefer >3 yr (>10 kg) LPV/r or SQV/r or SQV/NFV or NFV

13. Alternative ARV Choices for Pediatric Patients 1 st Line ARVConsiderations2 nd Line ARV 3 NRTI Combo (choose 3 except do not use AZT/d4T): NRTI : 3TC or AZT [d4T] Minimal toxicity Anemia Lipodystrophy/lactic acidosis/ peripheral neuropathy ddI (+ 3TC?) or ABC Hypersensitivity reaction PLUS a PI: LPV/r or SQV/r or SQV/NFV or NFV* PLUS an NNRTI: NVP or EFV

15. Example of Weight-Based Dosing Table for Children Including Pediatric and Adult Formulations Weight (kg) Nevirapine syrupNevirapine tablets 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 5-6.924.5 7-9.93.57 10-11.948 12-14.9510½ am only½ am and pm 15-19.97141 am or ½ am or pm1 am and ½ pm 20-29.9½ am and pm1 am and pm 30-34.91 am and pm

16. 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.

17. Baseline and Monitoring Pediatric ARV BaselineOn ARV Confirm dxN/A Clinical stage ReadinessAdherence Concom conditions/meds Wt, ht, developWt, Ht, growth, development 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 labSx-directed, eg ALT, lipid, glucose VL if availableVL if indicated (to confirm CD4 drop?)

18. 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?

19. 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).

20. 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

21. 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.

22. Potential Proposal to Use Clinical Staging to Decide on Switch Due to Treatment Failure Clinical stageConsiderations 1No 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

23. 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.

24. 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?

25. Changes to Ped Guidelines: TB and ARV TB and ARV: –What ARV to start (or to change if on 1 st 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)

26. Changes to Ped Guidelines: TB and ARV TB and ARV: –If on 2 nd 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).

27. 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

28. 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?