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Indications for Initiation of ARV Therapy in Children Age >1 Year Clinical Category AIDS (Clinical Category C) Mild-Moderate Symptoms (Clinical Category A or B) Asymptomatic (Clinical Category N) OR OR CD4+ Cell Percentage <15% (Immune Category 3) 15–25% (Immune OR Category 2) AND >25% AND (Immune Category 1) Plasma HIV RNA Copy Number Recommendation Any Value Treat >100,000 copies/mL2 Consider Treatment <100,000 copies/mL2 Many experts would defer therapy and closely monitor clinical, immune and viral parameters 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 Choice of Initial ARV Therapy The goals of ARV therapy are: • 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 Choice of Initial ARV Therapy The Working Group recommends: • Consideration of resistance testing before initiation of therapy in newly diagnosed infants <12 months • Particularly if mother has known or suspected drug-resistant virus Recommendations on ARV Regimens for Initial Therapy Working Group criteria: • 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 Types of ARV Regimens for Children • PI-based (2 NRTIs + PI) • NNRTI-based (2 NRTIs + NNRTI) • NRTI-based (3 NRTIs) Drug Regimen Categories for Initial Therapy • Strongly recommended • Recommended as an alternative • Offered in special circumstances • Not recommended • Insufficient data for recommendation PI-Based Regimens Advantages Disadvantages • Potent • High pill burden • NNRTI-sparing • Multiple drug interactions • Targets HIV at 2 steps • Resistance requires multiple mutations • Metabolic complications • Poor palatability • Few pediatric formulations Initial ARV Therapy: Recommended (PI-Based) Strongly recommended: Lopinavir/ritonavir or nelfinavir or ritonavir + 2 NRTIs1 Alternative recommendation: Amprenavir (children >4 years old)2 or indinavir + 2 NRTIs1 NNRTI-Based Regimens Advantages • Effective • Palatable • Less dyslipidemia/fat maldistribution • PI-sparing • Lower pill burden Disadvantages • Cross resistance among NNRTIs • Rare, but serious lifethreatening skin rashes • Hepatic toxicity • Multiple drug interactions Initial ARV Therapy: Recommended (NNRTI-Based) Strongly recommended: Alternative recommendation: •Children >3 years: Efavirenz3 + 2 NRTIs1 •Children <3 years or who cannot swallow capsules: Nevirapine3 + 2 NRTIs1 Nevirapine + 2 NRTIs in children >3 years old NRTI-Based Regimens Advantages Disadvantages • Spares other classes of drugs • May be less potent than other regimens • Minimal drug-drug interactions • Limited NRTI cross resistance • Palatable • Lower pill burden • Rare, but serious lactic acidosis/hepatic steatosis • Potential for ABC hypersensitivity Initial ARV Therapy: Recommended (NRTI-Based) Strongly recommended: None Alternative recommendation: Zidovudine + lamivudine + abacavir Use only in special circumstances: 2 NRTIs1 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 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) 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 11/26/03 AETC NRC 16 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 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 Immunologic Considerations for Changing ARV Therapy • • • 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) Clinical Considerations for Changing ARV Therapy • Progressive neurodevelopmental deterioration • Growth failure despite adequate nutritional support • Disease progression 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 Changing ARVs for Treatment Failure/Disease Progression • Assess and review adherence – • Perform resistance testing – • • • Review patient medications 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 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 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 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 Adherence Issues in Adolescents • Denial and fear of their HIV infection • Lack of belief in the effectiveness of ARV • Misinformation • Low self-esteem • Distrust of the medical establishment • Unstructured and chaotic lifestyle • Fear of ARV • Lack of familial and social support Adherence Issues in Adolescents • Adolescents’ readiness – Reminder systems, beepers, timers – Stylish pill boxes Conclusion Clinical care and treatment changes U.S. Pediatric Guidelines Working Group meets monthly and reviews clinical trials result Published text posted on www.aidsinfo.nih.gov Current slide set with speaker notes posted on www.aidsetc.org