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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Role of Therapeutic Drug Monitoring in Management of Pediatric HIV Infection
(Last updated: March 5, 2015; last reviewed: March 5, 2015)
Evaluation of plasma concentrations of antiretroviral drugs is not required in the management of most pediatric patients with HIV, but should be considered in children on combination antiretroviral therapy in the following scenarios (BII):
Use of antiretroviral drugs with limited pharmacokinetic data and therapeutic experience in children (e.g., for 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);
Suspected suboptimal absorption of the drug; or
Suspected dose-dependent toxicity.
Evaluation of the genetic G516T polymorphism of drug metabolizing enzyme cytochrome P450 (CYP450) 2B6 in combination with the evaluation of plasma efavirenz concentrations is recommended for children aged <3 years receiving efavirenz because the dosing recommendation depends on the result, given the significant association between this polymorphism and efavirenz concentrations (AII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion
† Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents
The goal of therapeutic drug monitoring (TDM) of antiretroviral (ARV) drugs is to optimize treatment responses and tolerability, and to minimize drug-associated toxicity. A number of adult studies suggest that modified doses and regimen choices based on TDM result in achievement of targeted ARV drug concentrations and are associated with improved clinical response and/or tolerability.1-7 In children, the usefulness of TDM to guide dosing of ARV drugs has been demonstrated in a number of non-randomized clinical trials and case reports.8-19
Dosing of ARV drugs in HIV-infected children and adolescents depends on chronological age and/or body parameters (e.g., height, weight). Ongoing growth requires continuous reassessment of dosing of ARV drugs in order to avoid low drug exposure and development of viral resistance and virologic failure. Developmental differences in drug absorption, distribution, metabolism, and elimination contribute to high variability and a greater frequency of suboptimal exposure to multiple therapeutic agents including ARVs in children and adolescents compared to adults.20-22 Suboptimal exposure to selected ARV agents with recommended dosing has been demonstrated in pediatric patients, especially in young children.14,15,23-25
Because of the diverse developmental challenges in palatability and acceptability of combination antiretroviral therapy (cART), children and adolescents are frequently faced with the use of altered dosing regimens and ARV combinations for which safety and efficacy have not been established in large clinical trials. Furthermore, dosing recommendations for ARV drugs at the time of licensing for pediatric use are frequently derived from a limited number of patients and pharmacokinetic (PK) modeling and may be revised as newer PK data become available.14,15,24 The Health and Human Services (HHS) Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children (the Panel) recommends considering TDM for certain ARV agents when the newly approved pediatric formulation and/or dosing are used based on limited PK and efficacy data in small populations (see specific drug information sections). TDM can also be considered in management of treatment failure for children on cART to increase efficacy and to decrease toxicity.
Use of Therapeutic Drug Monitoring to Improve Efficacy
The relationship between ARV drug concentrations and ARV efficacy must be clearly defined for TDM to be useful.26-29 This association has been shown to be the strongest for protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) as well as for the CCR5 receptor antagonist maraviroc.19,30-32 For nucleoside reverse transcriptase inhibitors (NRTIs), intracellular concentrations of their triphosphate metabolites have been shown to be most important in determining therapeutic response. Obtaining intracellular NRTI metabolite concentrations is expensive, labor-intensive, requires large blood volumes, and is limited to research settings. Limited data have demonstrated that serum concentrations of NRTIs are also correlated with virologic suppression; however, no efficacy plasma concentrations have been derived for NRTIs.33,34
Based on data from adult studies, consensus target efficacy plasma trough concentrations for treatment-naive and treatment-experienced patients have been developed by clinical pharmacology experts from the United States and Europe for the many PIs and NNRTIs, as well as the CCR5 receptor antagonist maraviroc (see Table 18). Several of these targets (lopinavir, nelfinavir, efavirenz, nevirapine) have been validated in pediatric studies. Efficacy trough concentrations for maraviroc and tipranavir have been derived in patients with multiple drug-resistant HIV strains only. Although exposure-response data for the PI darunavir, the NNRTI etravirine, and the integrase inhibitor raltegravir are accumulating, they have been considered insufficient to define target efficacy concentrations at this time.35-38 Table 18 includes data on the plasma trough concentrations derived from clinical trials of these drugs.
Table 18. Target Trough Concentrations of Antiretroviral Drugsa
d Suggested median plasma trough concentration in treatment-experienced patients with resistant HIV-1 strain only
e Darunavir dose 600 mg twice daily
f Median (range)
The suggested efficacy plasma trough concentrations are generally applicable when the patient’s resistance testing demonstrates susceptibility to the particular ARV drug. In treatment-experienced patients with virologic failure, a higher plasma trough concentration may be required to suppress viral replication when there is decreased susceptibility to the ARV drug.9,39-41 Recent PK/pharmacodynamic modeling of lopinavir/ritonavir in children suggests that higher plasma exposure might be beneficial not only for treatment-experienced, but also for treatment-naive children, with the target plasma trough concentration of 2,400 ng/mL corresponding to C95 proposed as a target for increased efficacy.42 For the majority of PIs, viral resistance develops cumulatively with successive mutations, and higher drug exposure can potentially overcome lower levels of resistance. The concept of inhibitory quotient (IQ) has been developed and successfully applied to certain PIs.43 IQ is expressed as the ratio of patient plasma trough concentration (Cmin) to specific viral susceptibility parameters (e.g., fold change in inhibitory concentration or the number of drug-specific resistance-associated mutations).1,39 This approach does not apply to drugs with low, single mutation thresholds for resistance (e.g., the NNRTIs nevirapine and efavirenz) because it is not possible to overcome such resistance by increasing the ARV drug exposure. Suboptimal plasma concentrations of efavirenz and nevirapine have been linked to virologic failure in children.8,24,44 Evaluation of efavirenz plasma concentrations in combination with pharmacogenetic evaluation for the polymorphism of the main drug metabolizing enzyme cytochrome P (CYP) 450 CYP2B6 is recommended if efavirenz is used in children aged <3 years to avoid suboptimal drug exposure (see Efavirenz in Appendix A: Pediatric Antiretroviral Drug Information).
Use of Therapeutic Drug Monitoring to Decrease Toxicity
The exposure-toxicity response relationship has been well defined for the PIs indinavir and atazanavir and the NNRTI efavirenz.28,45 Increased plasma concentrations of atazanavir have been linked to elevated bilirubin concentrations in adolescents, and measurement of the atazanavir plasma concentrations has been suggested for management of the atazanavir-associated hyperbilirubinemia in adolescents.45
Adverse central nervous system (CNS) effects (e.g., CNS depression, dizziness, insomnia, hallucinations) associated with efavirenz have been shown to correlate with efavirenz plasma trough concentrations >4 mcg/mL in adult and pediatric studies.8,46,47 TDM-guided reduction in the efavirenz dose has been shown to successfully reduce neuropsychiatric side effects while allowing for continued virologic suppression in prospective adult studies.48,49 Recent reports on the PK of efavirenz in children aged <3 years demonstrated a significant relationship between high plasma efavirenz median concentrations and area under the curve versus time concentration (AUC) and drug-associated hematologic and CNS toxicity.10,50 Evaluation of the efavirenz plasma concentrations in combination with determination of polymorphism of the main drug-metabolizing enzyme CYP2B6 should be considered for preventing and decreasing efavirenz-associated adverse events in children aged <3 years and might be considered in older children (see next section on pharmacogenetics).
Pharmacogenetic Evaluation as Part of Therapeutic Drug Monitoring
The pharmacogenetics of HIV therapy investigate the interactions between human genetic polymorphisms and PK and the outcome of cART. Multiple metabolizing and drug transporter genes have been studied for their association with efficacy and toxicity of ARV drugs. The most clinically significant relationship is demonstrated by the association between the CYP2B6 G to T polymorphism and the PK, toxicity and clinical response to efavirenz. CYP2B6 T516T and G516T genotypes have been associated with elevated plasma efavirenz concentrations and CNS toxicity in children and adults, while CYP2B6 G516G genotype has been linked to low plasma concentrations of efavirenz, decreased rates of virologic suppression and development of resistance.10,47,51,52 Reducing the efavirenz dose in patients with the CYP2B6 T516T genotype has been shown to reverse or decrease drug-associated toxicity in adults and adolescents and to achieve therapeutic efavirenz concentrations.9,49,53,54
The effect of CYP2B6 G516T polymorphism on the PK of efavirenz appears to be most pronounced in younger children undergoing maturation of the CYP450 enzymatic system.10,21,50 In the ongoing PACTG P1070 study, efavirenz dosing of approximately 40 mg/kg in children aged <3 years produced therapeutic efavirenz plasma concentrations in 68% of children with GG/GT 516 rapid CYP2B6 genotypes, while the same dose led to significantly higher exposure with treatment-related toxicities greater than grade 3 in children with TT 516CYP2B6 genotype.10 In this ongoing study, genotyping for CYP2B6 G516T polymorphism is incorporated in the pretreatment evaluation and will be used to determine the dosing regimen. While efavirenz is not recommended for initial therapy in children aged <3 years, should efavirenz use be considered in children aged <3 years, the Panel recommends obtaining CYP2B6 genotype as part of pretreatment evaluation and dose selection (see Efavirenz in Appendix A: Pediatric Antiretroviral Drug Information). For children aged >3 years with a known CYP2B6 poor metabolizer genotype, reduction of the recommended efavirenz dose may be considered. This dose reduction may prevent the risk or decrease the grade of CNS toxicity; however, it may also increase pill burden, particularly among adolescents who are using efavirenz-based fixed-dose combinations. If this approach is taken, subsequent TDM is recommended to ensure that the patient achieves recommended plasma trough therapeutic efavirenz concentrations.49,55
The use of TDM in clinical practice poses multiple challenges, including availability of the ARV drug assays and certified laboratories; difficulties in collecting timed blood samples in children to obtain true plasma trough concentrations; prolonged time to obtain the results; limited availability of pharmacologic pediatric expertise; and cost and reimbursement considerations. More extended PK evaluation of the AUC in children involves higher volumes of blood samples, cost, and time commitment. Limited information on safety and effectiveness of dose adjustment strategies in children and adolescents may also limit the application of TDM in clinical practice.
When obtaining plasma concentrations in pediatric and adolescent patients, several important steps need to be taken. The accurate interpretation of TDM requires documentation of the following elements:
Accurate information about the dose and formulation
List of concomitant medications
Food intake with the dose
Timing of the dose and blood sample collection
Adherence and resistance information
Additional practical suggestions on TDM of ARV drugs can be found in a position paper by the Adult AIDS Clinical Trials Group Pharmacology Committee26 and several pediatric review manuscripts.13,56 Most importantly, consultation with an expert in pediatric HIV pharmacology is required to obtain guidance on when to obtain samples for TDM, how to interpret the PK data, and how to evaluate the need for dose adjustment and repeat PK evaluation and follow up.
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