1. Indications for Initiation of ARV Therapy in Children Age >1 Year Clinical Category CD4 + Cell Percentage Plasma HIV RNA Copy Number Recommendation AIDS (Clinical Category C) OR <15% (Immune Category 3) Any Value Treat Mild-Moderate Symptoms (Clinical Category A or B) OR 15–25% (Immune Category 2) OR >100,000 copies/mL 2 Consider Treatment Asymptomatic (Clinical Category N) AND >25% (Immune Category 1) AND <100,000 copies/mL 2 Many experts would defer therapy and closely monitor clinical, immune and viral parameters

2. Choice of Initial ARV Therapy Use ZDV monotherapy only for prophylaxis in indeterminate infant in first 6 weeks of life Use combination ARV therapy with at least 3 drugs Slows disease progression Improves survival Sustains virologic response better Delays development of resistance

3. Choice of Initial ARV Therapy Maximal suppression of viral replication to undetectable levels, if possible, for as long as possible Preservation or restoration of immune function Prevention of complications of HIV infection, including opportunistic infections The goals of ARV therapy are:

4. Choice of Initial ARV Therapy Consideration of resistance testing before initiation of therapy in newly diagnosed infants <12 months Particularly if mother has known or suspected drug-resistant virus The Working Group recommends:

5. Recommendations on ARV Regimens for Initial Therapy Data demonstrating durable viral suppression, immunologic and clinical improvement Incidence and types of drug toxicity Availability/palatability of formulations for children Dosing frequency, food and fluid needs Potential for drug interactions Working Group criteria:

6. Types of ARV Regimens for Children PI-based (2 NRTIs + PI) NNRTI-based (2 NRTIs + NNRTI) NRTI-based (3 NRTIs)

7. Drug Regimen Categories for Initial Therapy Strongly recommended Recommended as an alternative Offered in special circumstances Not recommended Insufficient data for recommendation

8. PI-Based Regimens Advantages Potent NNRTI-sparing Targets HIV at 2 steps Resistance requires multiple mutations Disadvantages High pill burden Multiple drug interactions Metabolic complications Poor palatability Few pediatric formulations

9. Initial ARV Therapy: Recommended (PI-Based) Strongly recommended: Lopinavir/ritonavir or nelfinavir or ritonavir + 2 NRTIs 1 Alternative recommendation: Amprenavir (children >4 years old) 2 or indinavir + 2 NRTIs 1

10. NNRTI-Based Regimens Advantages Effective Palatable Less dyslipidemia/fat maldistribution PI-sparing Lower pill burden Disadvantages Cross resistance among NNRTIs Rare, but serious life- threatening skin rashes Hepatic toxicity Multiple drug interactions

11. Initial ARV Therapy: Recommended (NNRTI-Based) Strongly recommended: Children >3 years: Efavirenz 3 + 2 NRTIs 1 Children <3 years or who cannot swallow capsules: Nevirapine 3 + 2 NRTIs 1 Alternative recommendation: Nevirapine + 2 NRTIs in children >3 years old

12. NRTI-Based Regimens Advantages Spares other classes of drugs Minimal drug-drug interactions Limited NRTI cross resistance Palatable Lower pill burden Disadvantages May be less potent than other regimens Rare, but serious lactic acidosis/hepatic steatosis Potential for ABC hypersensitivity

13. Initial ARV Therapy: Recommended (NRTI-Based) Strongly recommended: None Alternative recommendation: Zidovudine + lamivudine + abacavir Use only in special circumstances: 2 NRTIs 1

14. Initial ARV Therapy: Not Recommended Monotherapy—except ZDV prophylaxis for HIV exposed infants during the first 6 weeks of life Certain 2 NRTI combinations –Antagonistic: ZDV/d4T –Overlapping toxicities: d4T/ddC, ddI/ddC, 3TC/ddC –Similiar structure and identical resistance: 3TC/FTC Saquinavir: requires RTV boosting to achieve adequate drug level; pediatric dose unknown

15. Initial ARV Therapy: Insufficient Data to Recommend Two NRTIs + delavirdine Dual PIs (except lopinavir/ritonavir) NRTI + NNRTI + PI (except EFV + NFV + 1 or 2 NRTIs) Regimens containing –Emtricitabine (FTC) –Tenofovir –Atazanavir –Fosamprenavir –Tipranavir/ritonavir –Enfuvirtide (T-20)

16. 11/26/03AETC NRC16 Changing ARV Therapy Failure based on virologic, immunologic, or clinical parameters Toxicity or intolerance on the current therapy Consider change if there is new data demonstrating that another regimen is superior to the current regimen

17. Virologic Considerations for Changing ARV Therapy Less than 1.0 log10 decrease in HIV RNA from baseline 8-12 weeks after start of ARV therapy HIV RNA not suppressed to undetectable levels after 4-6 months Repeated detection in HIV RNA levels after undetectable levels on ARVs A reproducible increase in HIV RNA after substantial response

18. Monitoring Virologic Response to Therapy Change Assess virologic response within 4 weeks after initiating or changing therapy Measure HIV RNA levels at least every 3 months Resistance testing is recommended for persistent or increasing HIV RNA levels

19. Change in immune classification For children with <15% CD4 +, persistent decline of ≥5% Rapid and substantive decrease in CD4 + count (ie, >30% decline in <6 months) Immunologic Considerations for Changing ARV Therapy

20. Clinical Considerations for Changing ARV Therapy Progressive neurodevelopmental deterioration Growth failure despite adequate nutritional support Disease progression

21. Changing ARVs for Toxicity/Intolerance Choose drugs from same class with different toxicity/side effect profiles Change of a single drug is permissible if a single drug can be identified as a cause of toxicity Do not reduce dose below lower end of therapeutic dose range for the particular drug

22. Changing ARVs for Treatment Failure/Disease Progression Assess and review adherence – Review patient medications Perform resistance testing – Consider overlap in resistance Change ARVs to contain at least 2 or 3 new ARVs Consider clinical trials of investigational ARVs Discuss quality of life issues

23. Adherence is Critical ARV most effective in initial therapy Poor adherence may enhance drug resistance Child and caregiver participation is crucial Assess, discuss and address adherence issues before initiating therapy

24. Adherence Issues in Children Availability of drugs in palatable, liquid or mixable formulations Difficulty of giving drugs that have food restrictions, because of children’s (particularly infant) eating schedules Children’s dependence on caregivers for administration

25. Adherence Issues in Children Timing issues, e.g., during school hours Families’ reluctance to disclose HIV diagnosis may limit medication administration at daycare/school Children’s developmental level influences ability and willingness to take medications

26. Adherence Issues in Adolescents Denial and fear of their HIV infection Misinformation Distrust of the medical establishment Fear of ARV Lack of belief in the effectiveness of ARV Low self-esteem Unstructured and chaotic lifestyle Lack of familial and social support

27. Adherence Issues in Adolescents Adolescents’ readiness – Reminder systems, beepers, timers – Stylish pill boxes

28. Conclusion n Clinical care and treatment changes n U.S. Pediatric Guidelines Working Group meets monthly and reviews clinical trials result n Published text posted on www.aidsinfo.nih.gov www.aidsinfo.nih.gov n Current slide set with speaker notes posted on www.aidsetc.orgwww.aidsetc.org