The FDA has approved a new pediatric dosage form and label changes for atazanavir. Please see the FDA announcement for more information.
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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
What's New in the Guidelines
(Last updated: February 12, 2014; last reviewed: February 12, 2014)
Key changes made by the Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children (the Panel) to update the November 1, 2012, Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection are summarized below. Some content has been reorganized and condensed to enhance usability. Throughout the document, text and references have been updated to include new publications where relevant. The terms “mother-to-child transmission (MTCT)” and “prevention of mother-to-child transmission (PMTCT)” have been replaced with “perinatal transmission” and “prevention of perinatal transmission,” respectively. Minor revisions have been made in toxicity tables and other sections of the document; all changes are highlighted throughout the PDF version of the guidelines. A link to the Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children (published November 6, 2013), has been inserted in selected areas of the text to refer readers to more detailed information about use of specific antiretroviral (ARV) agents in the context of hepatitis B, hepatitis C, or tuberculosis coinfection (see the Pediatric Opportunistic Infections Guidelines).
Diagnosis of HIV Infection
To address the possibility that the sensitivity of diagnostic virologic assays in HIV-exposed infants might be affected by combination ARV prophylaxis, the Panel recommends if the results of prior virologic testing were negative while an infant was receiving prophylaxis, virologic diagnostic testing should be considered 2 to 4 weeks after cessation of ARV prophylaxis for infants receiving combination ARV infant prophylaxis (BIII).
Clinical and Laboratory Monitoring of Pediatric HIV Infection
Two former sections titled Laboratory Monitoring of Pediatric HIV Infection Prior to Therapy Initiation and Monitoring Children on Antiretroviral Therapy have been combined into a single section with revisions that reflect this modification.
The Panel now recommends that CD4 T lymphocyte (CD4) cell count/percentage can be monitored less frequently (every 6 to 12 months) in children and youth who are adherent to therapy, and who have CD4 levels well above the threshold for opportunistic infection risk, sustained viral suppression, and stable clinical status for more than 2 to 3 years (BII).
The Panel has reviewed and updated the schedule for clinical and laboratory monitoring of children before and after initiation of combination antiretroviral therapy (cART) in Table 3.
When to Start Antiretroviral Therapy
The Panel provides information related to the recent report of “functional cure” in an HIV-infected child in Mississippi, discusses the lack of pharmacokinetic (PK) and safety data for most drugs in preterm infants and infants aged <2 weeks, recommends that providers considering treatment for these groups contact a pediatric HIV expert for guidance, and notes that if early treatment is initiated and a child is shown to be infected, the Panel does not recommend empiric treatment interruption unless the durability of the findings in the Mississippi baby can be replicated. In addition, the Panel recommends initiation of cART in children of all ages with HIV RNA levels >100,000 copies/mL (AII).
What Drugs to Start: Initial Combination Therapy for Antiretroviral Treatment-Naive Children
This section has been reorganized, and some content has been moved to a new, separate section about what drugs should not be started in ARV-naive children.
Once-daily darunavir in combination with ritonavir is now recommended as a component of a once-daily regimen in adolescents aged ≥12 years.
Raltegravir, an integrase strand inhibitor (INSTI), is now considered as an agent for Use in Special Circumstances for initial therapy in a cART regimen for ARV-naive pediatric patients despite limited data in children, because of its favorable safety profile, lack of significant drug interactions, and palatability.
The Panel suggests that clinically stable children with undetectable viral load and stable CD4 counts for more than 6 months can switch from twice-daily to once-daily abacavir as a component of a once-daily regimen.
The Panel modified its recommendation for fosamprenavir in combination with ritonavir in children aged ≥6 months from “Alternative Option” to “Use in Special Circumstances” due to concerns about the required volume of the liquid formulation and the availability of other Alternative regimens without such problems.
A section has been added on special considerations for treatment of premature infants and infants younger than age 15 days, discussing lack of PK data to define appropriate dosing in this age group, and consultation with a pediatric expert is recommended if providers consider treating such infants.
What Not to Start: Regimens Not Recommended for Initial Therapy of Antiretroviral-Naive Children
A new table has been added summarizing the rationale for not recommending specific ARV regimens or components for initial therapy (see Table 8).
Management of Children Receiving Combination Antiretroviral Therapy
The former section on “Management of Treatment-Experienced Infants, Children, and Adolescents Receiving Antiretroviral Therapy” has been retitled and restructured into 3 sections:
Modifying ARV regimens in children on effective cART for simplification or improved adverse effect profile
Recognizing and managing treatment failure
Considerations about interruptions in therapy.
New guidance and a new table (Table 12) is provided about modifying ARV regimens for reasons of improved pill burden, palatability, tolerability, and use of once-daily dosing in children with sustained virologic suppression on their current regimen. The Panel now recommends that changing to a new regimen should be considered in children who have sustained virologic suppression on their current regimen, in order to facilitate continued adherence and increase safety (BII).
The Panel has added a recommendation indicating that outside of the context of a clinical trial structured interruptions of cART are not recommended in the clinical care of HIV-infected children (AIII).
Role of Therapeutic Drug Monitoring in the Management of Pediatric HIV Infection
This section has been expanded to provide graded strength recommendations on evaluating plasma concentrations for ARV treatment-naive and treatment-experienced children.
Evaluation of plasma concentrations of ARV drugs, while not routinely required in the management of HIV-infected pediatric patients, should be considered in children on ART in the following scenarios: (BII)
Use of ARV drugs with limited PK data and therapeutic experience in children (e.g., use of efavirenz in children aged <3 years and darunavir with once-daily dosing in children aged <12 years)
Significant drug-drug interactions and food-drug interactions
Unexpected suboptimal treatment response (e.g., lack of virologic suppression with history of medical adherence and lack of resistance mutations)
Suspected suboptimal absorption of the drug
Suspected dose-dependent toxicity
Specific recommendations for monitoring plasma concentrations are provided for use of efavirenz in children aged <3 years and darunavir with once-daily dosing in children aged <12 years.
Evaluation of the genetic G516T polymorphism of drug metabolizing enzyme cytochrome P450 (CYP450) 2B6 is also recommended for children aged <3 years receiving efavirenz because of the significant association of this polymorphism with drug concentrations (AII).
Antiretroviral Drug Resistance Testing
Table 17, summarizing recommendations for use of available resistance testing, has been added.
Pediatric Antiretroviral Drug Information
Updates with new pediatric data are provided when relevant to specific drugs. Subheadings have been added to the Pediatric Use section to enhance the ability to locate specific information.
Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors
Abacavir: The Panel provides recommendations on once-daily dosing of abacavir in children. In clinically stable children with undetectable viral loads and stable CD4 cell counts for more than 6 months, switching from twice-daily to once-daily dosing of abacavir (at a dose of 16 to 20 mg/kg/dose to maximum of 600 mg once daily) is recommended as part of a once-daily regimen.
Efavirenz: The Food and Drug Administration (FDA) has approved efavirenz for use in infants and children aged ≥3 months and weighing ≥3.5 kg. However, the Panel recommends that efavirenz generally not be used in children aged 3 months to <3 years because of insufficient data on dosing, and concerns about the potential for underdosing or excessive exposure associated with the CYP 2B6 genotype. Information is provided about use in children aged 3 months to <3 years, including evaluation of the CYP 2B6 genotype prior to dosing and therapeutic drug monitoring. Instructions have been added about the use of capsules as a sprinkle preparation with food or formula.
Nevirapine: The Panel provides information on the newly available 100-mg extended release (XR) tablets and nevirapine XR dosing in children aged ≥6 years. Supporting information and consideration of initiating full-dose nevirapine (rather than lead-in dosing) in children are discussed. The Panel recommends that children aged >6 years who are already taking immediate-release nevirapine twice daily can be switched to nevirapine XR without lead-in dosing as long as plasma RNA is undetectable. A new section has been added to discuss the potential use of nevirapine in HIV-infected infants aged < 14 days or in premature infants.
Atazanavir: Modifications have been made in the dosing table because the 250-mg dose is no longer achievable with currently available capsule dose strengths; 100-mg capsules have been discontinued. The panel discusses new dosing recommendations and notes that some experts would increase the atazanavir dose to 300 mg for children weighing ≥35 kg to avoid underdosing, especially when administered with tenofovir, which decreases plasma atazanavir concentrations.
Darunavir: In February 2013, the FDA approved once-daily dosing of darunavir in children aged >3 years and weight >10 kg, based on population PK modeling. A pediatric trial evaluating once-daily darunavir with ritonavir dosing in children aged 6 to <12 years has not been conducted and no efficacy data have been obtained. Therefore, the Panel recommends that once-daily darunavir with ritonavir should be used only in treatment-naive and treatment-experienced adolescents aged ≥12 years without darunavir resistance-associated mutations. Twice-daily dosing of darunavir with ritonavir should continue to be used in children aged >3 years and <12 years.
Integrase Strand Transfer Inhibitors
Dolutegravir: Information has been added on dolutegravir, which is now FDA-approved for use in adults and children aged ≥12 years and weight ≥40 kg who are treatment-naive or treatment-experienced and integrase strand transfer inhibitor (INSTI)-naive. The Panel notes that dolutegravir is not approved for use in children aged <12 years, but that a clinical trial in treatment-experienced children aged <12 years is under way.
Raltegravir: Raltegravir is now available as an oral suspension that has been FDA-approved for use in infants and children aged ≥4 weeks and weighing 3 kg to <20 kg. This formulation is supplied as a single-use packet to be reconstituted and used within 30 minutes of mixing; unused solution should be discarded.