Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
What's New in the Guidelines
(Last updated:8/11/2011)
What’s New in the Pediatric Guidelines?
Key changes made to update the August 16, 2010, Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection are summarized below. All of the changes are highlighted in the guidelines. Throughout the document, references have been updated to include new publications where relevant.
When to Start Antiretroviral Therapy
Antiretroviral-naive HIV-infected infants 12 months or younger
• Antiretroviral therapy (ART) continues to be recommended for all infants younger than 12 months of age regardless of clinical, immunologic, or virologic symptoms. The Panel believes that although it is important to assess, discuss, and address issues associated with adherence with the infant’s caregivers, it is very important to expedite this assessment for young infants given the high risk of disease progression and mortality in young HIV-infected infants.
Antiretroviral-naive HIV-infected children 1 year or older
• Current adult ART guidelines are discussed, along with similarities and differences between guidelines for children and adults. The CD4 threshold for recommending ART in children ages ≥5 years with minimal or no clinical symptoms has been increased from <350 cells/mm3 to <500 cells/mm3.
o The evidence for this recommendation is strongest for children with CD4 counts <350 cells/mm3 (AI*).
o For children with CD4 counts 350–500 cells/mm3 (BII*), the recommendation is based on observational data in adults; hence the evidence base is not as strong. The Panel’s recommendations should not prohibit research studies in children designed to answer this question more definitively.
• Treatment is also recommended for children with minimal or no clinical symptoms and normal immune status (CD4 percentage >25% if age 1 to <5 years, or CD4 count >500 cells/mm3 if age ≥5 years) if plasma HIV RNA is ≥100,000 copies/mL (BII*).
• Treatment may be considered for children age ≥1 year with normal immune status (CD4 percentage >25% if age 1 to <5 years, or CD4 count >500 cells/mm3 if age ≥5 years) and plasma HIV RNA <100,000 copies/mL (CIII).
• Because of slower disease progression among older children without symptoms of advanced disease, it is important to take time to educate both the caregiver and child about the need for adherence to the regimen and to resolve potential adherence problems before initiation of therapy. This is particularly true for children age ≥5 years given their lower risk of disease progression and the higher CD4 count threshold now recommended for initiating therapy.
What to Start
• The section has been reorganized to include a general discussion of factors to consider when selecting an initial antiretroviral (ARV) regimen for children and a specific discussion regarding the choice of a non-nucleoside reverse transcriptase inhibitor (NNRTI)- versus a protease inhibitor (PI)-based initial regimen, citing recent results from pediatric clinical trials (PENPACT I [PENTA 9/PACTG 390] and P1060).
• The preferred initial therapy for all infants and children ages ≥14 days to <3 years is lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (NRTIs) (AI), with nevirapine-based regimens now considered an alternative regimen for initial therapy in this age group (AI). Based on new data on toxicity in preterm infants, lopinavir/ritonavir should not be administered to neonates before a postmenstrual age of 42 weeks and a postnatal age of at least 14 days.
• For initial therapy for children age ≥6 years, atazanavir with low-dose ritonavir boosting has been added as a second preferred PI choice (AI*), joining lopinavir/ritonavir (AI).
• Preferred dual-NRTI backbone regimens for initial therapy include abacavir plus lamivudine or emtricitabine in children age ≥3 months (AI), tenofovir plus lamivudine or emtricitabine for adolescents age ≥12 years and Tanner Stage 4 or 5 (AI*), or zidovudine plus lamivudine or emtricitabine at any age (AI*).
• Two new alternative dual-NRTI backbone regimens for initial therapy have been added: didanosine plus lamivudine or emtricitabine at any age (BI*) or tenofovir plus lamivudine or emtricitabine for adolescents age ≥12 years and Tanner Stage 3 (BI*).
• One new dual-NRTI backbone regimen for initial therapy in special circumstances has been added: tenofovir plus lamivudine or emtricitabine for adolescents age ≥12 years and Tanner Stage 2.
• Rilpivirine-containing regimens are currently not recommended for initial therapy in children because of lack of data on pediatric dosing and safety and lack of pediatric formulation.
Monitoring
• It is noted that temporary viral load elevations between the level of detection and 1,000 copies/mL (“blips”) are often detected in adults and children on treatment and should not be considered viral failure.
• Urinalysis (UA) has been added as a recommended baseline laboratory evaluation, with re-evaluation every 6–12 months.
Toxicity
• New sections have been added to Table 17, Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations, on (1) central nervous system (CNS) toxicity, (2) gastrointestinal (GI) effects, (3) nephrotoxicity, and (4) peripheral nervous system toxicity. Existing sections have been updated.
Treatment Failure
• A new section discussing management of children with ongoing adherence problems as the reason for viral failure has been added. The use of lamivudine or emtricitabine alone as an interim “bridging regimen” in the special circumstance of children with treatment failure associated with drug resistance and persistent nonadherence is discussed.
Resistance Testing
• Phenotypic resistance testing (usually in addition to genotypic resistance testing) is recommended for patients with known or suspected complex drug resistance mutation patterns, which generally arise after viral failure of successive ARV regimens.
• Genotypic assays to detect mutations associated with CXCR4 or D/M tropic virus (Trofile-DNA) are discussed.
Pediatric Antiretroviral Drug Information
The section has been reorganized to improve readability. Updates with new pediatric data are provided when relevant for specific drugs.
• Abacavir: Once-daily abacavir dosing (16 mg/kg/day, maximum 600 mg once daily) may be considered in clinically stable children with undetectable viral load and stable CD4 count. A table comparing the steady-state pharmacokinetics (PKs) from five pediatric clinical trials of abacavir when dosed once or twice daily has been added.
• Lamivudine: Once-daily lamivudine (300 mg once daily) may be used for adolescents age ≥16 years who weigh ≥50 kg. A table comparing the steady-state PKs from three pediatric clinical trials of lamivudine when dosed once or twice daily has been added.
• Stavudine: Use of a lower dose of stavudine (30 mg twice daily regardless of weight) in adults and older adolescent is discussed.
• Tenofovir: An update on the effect of tenofovir on bone mineral density (BMD) and renal function in children has been added.
• Efavirenz: Interpatient variability in efavirenz exposure secondary to polymorphisms in cytochrome P (CYP)450 genes is discussed; therapeutic drug monitoring (TDM) can be considered for management of efavirenz-related toxicity.
• Etravirine: Pediatric investigational dosing for etravirine in children ≥6 years of age is discussed.
• Nevirapine: Extended-release nevirapine is newly available for adults but is not approved for use in children age <18 years because of lack of data in this age group.
• Rilpivirine: Drug information on rilpivirine is added; there are no pediatric data available at this time.
• Darunavir: Once-daily dosing of darunavir is not recommended for children age <12 years or any child age <18 years who is treatment experienced; once-daily dosing (darunavir 800 mg plus ritonavir 100 mg) may be considered for treatment-naive pediatric patients age 12–18 years who weigh >40 kg.
• Lopinavir/ritonavir: Due to cardiovascular toxicity observed in preterm infants, lopinavir/ritonavir should not be administered to neonates before a postmenstrual age of 42 weeks and a postnatal age of at least 14 days.
• Saquinavir: Pretherapy electrocardiogram (ECG) is recommended for a patient initiating saquinavir-based therapy because significant PR and QT prolongation has been observed; saquinavir is not recommended for individuals with prolonged QT interval or those receiving other drugs that may prolong the QT interval.