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 1, 2016; Last Reviewed: March 1, 2016
|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. TDM may be useful in clinical management with drugs that have a known exposure-response relationship and a relatively narrow therapeutic window of desirable concentrations. The therapeutic window is a range of concentrations that are associated with the greatest likelihood of achieving the desired therapeutic response and/or reducing the frequency of drug-associated adverse reactions in clinical investigations. While many ARV drugs (e.g., most protease inhibitors, first-generation non-nucleoside reverse transcriptase inhibitors, the CCR5 receptor antagonist maraviroc) have target plasma trough concentrations associated with viral efficacy, only a few ARV drugs have drug levels associated with toxicity (e.g., nevirapine and efavirenz). Most TDM targets have been established in adult studies, but several drugs (e.g., lopinavir, nelfinavir, efavirenz, nevirapine) have had target concentrations validated in pediatric studies. The suggested efficacy plasma trough concentrations are generally applicable when resistance testing demonstrates susceptibility of the patient’s virus to the particular ARV drug. Table 17 includes data on the efficacy plasma trough concentrations derived from adult clinical trials of the ARV drugs. Currently, most TDM target concentrations for ARV drugs focus on reaching a trough or minimum concentration (Cmin).1 Population average Cmin for all ARV drugs can be found in the Food and Drug Administration-approved product labels.
|Established Efficacy Plasma Trough Concentrations|
|a Adapted from: Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2014.|
|b Measurable amprenavir concentration|
|c Measurable active (M8) metabolite|
|d Suggested median plasma trough concentration in treatment-experienced patients with resistant HIV-1 strain only|
Several adult and pediatric studies have suggested that TDM can have some utility to guide dosing of ARV drugs.1-10 Despite this evidence, the routine use of TDM in adult and pediatric patients is not recommended for the following reasons: lack of prospective studies that demonstrate improved clinical outcomes, uncertain target ranges for most ARV drugs, high intrapatient variability in drug concentrations, and a lack of commercial laboratories willing to provide real-time quantitation of ARV plasma concentrations.
There are special considerations with dosing of ARV drugs in HIV-infected children compared to adults, including dependence on chronologic 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 ARV drugs in children (particularly very young children) and adolescents compared to adults.11-13 Suboptimal exposure to selected ARV agents with recommended dosing has been demonstrated in pediatric patients, especially in young children.7,14,15
Pediatric ARV drug recommendations are often based on extrapolation of efficacy results from large clinical trials in adults, and dosing recommendations for ARV drugs at the time of pediatric drug approval are frequently derived from a limited number of patients and pharmacokinetic (PK) modeling, and may be revised as newer PK data become available.7 While the Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children does not recommend routine TDM for pediatric ARV therapy management, TDM can be considered for certain ARV agents when the approved pediatric formulation and/or dosing are based on limited PK and efficacy data in small populations (see specific drug information sections) or for certain clinical scenarios outlined in the text box above to ensure adequate drug concentrations and/or to decrease toxicity.
The accurate interpretation of TDM requires evaluation and documentation of the following:
- The dose and formulation
- Concomitant medications
- Food intake with the dose
- Timing of the dose relative to 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 Committee16 and pediatric TDM manuscripts.6,17 Most importantly, consultation with an expert in pediatric HIV pharmacology is strongly recommended 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.
- Pretorius E, Klinker H, Rosenkranz B. The role of therapeutic drug monitoring in the management of patients with human immunodeficiency virus infection. Ther Drug Monit. 2011;33(3):265-274. Available at http://www.ncbi.nlm.nih.gov/pubmed/21566505.
- Haas DW. Can responses to antiretroviral therapy be improved by therapeutic drug monitoring? Clin Infect Dis. 2006;42(8):1197-1199. Available at http://www.ncbi.nlm.nih.gov/pubmed/16575742.
- Perrone V, Cattaneo D, Radice S, et al. Impact of therapeutic drug monitoring of antiretroviral drugs in routine clinical management of patients infected with human immunodeficiency virus and related health care costs: a real-life study in a large cohort of patients. Clinicoecon Outcomes Res. 2014;6:341-348. Available at http://www.ncbi.nlm.nih.gov/pubmed/25053888.
- van Luin M, Kuks PF, Burger DM. Use of therapeutic drug monitoring in HIV disease. Curr Opin HIV AIDS. 2008;3(3):266-271. Available at http://www.ncbi.nlm.nih.gov/pubmed/19372977.
- Fletcher CV, Brundage RC, Fenton T, et al. Pharmacokinetics and pharmacodynamics of efavirenz and nelfinavir in HIV-infected children participating in an area-under-the-curve controlled trial. Clin Pharmacol Ther. 2008;83(2):300-306. Available at http://www.ncbi.nlm.nih.gov/pubmed/17609682.
- Rakhmanina NY, van den Anker JN, Soldin SJ, van Schaik RH, Mordwinkin N, Neely MN. Can therapeutic drug monitoring improve pharmacotherapy of HIV infection in adolescents? Ther Drug Monit. 2010;32(3):273-281. Available at http://www.ncbi.nlm.nih.gov/pubmed/20445485.
- Fillekes Q, Natukunda E, Balungi J, et al. Pediatric underdosing of efavirenz: a pharmacokinetic study in Uganda. J Acquir Immune Defic Syndr. 2011;58(4):392-398. Available at http://www.ncbi.nlm.nih.gov/pubmed/21926634.
- Neely MN, Rakhmanina NY. Pharmacokinetic optimization of antiretroviral therapy in children and adolescents. Clin Pharmacokin. 2011;50(3):143-189. Available at http://www.ncbi.nlm.nih.gov/pubmed/21294595.
- von Bibra M, Rosenkranz B, Pretorius E, et al. Are lopinavir and efavirenz serum concentrations in HIV-infected children in the therapeutic range in clinical practice? Paediatr Int Child Health. 2014;34(2):138-141. Available at http://www.ncbi.nlm.nih.gov/pubmed/24225343.
- Moholisa RR, Schomaker M, Kuhn L, et al. Plasma lopinavir concentrations predict virological failure in a cohort of South African children initiating a protease-inhibitor-based regimen. Antivir Ther. 2014;19(4):399-406. Available at http://www.ncbi.nlm.nih.gov/pubmed/24518130.
- Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology--drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157-1167. Available at http://www.ncbi.nlm.nih.gov/pubmed/13679531.
- Salem AH, Fletcher CV, Brundage RC. Pharmacometric characterization of efavirenz developmental pharmacokinetics and pharmacogenetics in HIV-infected children. Antimicrob Agents Chemother. 2014;58(1):136-143. Available at http://www.ncbi.nlm.nih.gov/pubmed/24145522.
- Winston A, Jose S, Gibbons S, et al. Effects of age on antiretroviral plasma drug concentration in HIV-infected subjects undergoing routine therapeutic drug monitoring. J Antimicrob Chemother. 2013;68(6):1354-1359. Available at http://www.ncbi.nlm.nih.gov/pubmed/23435690.
- Chadwick EG, Pinto J, Yogev R, et al. Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: pharmacokinetics and 24-week safety and efficacy. Pediatr Infect Dis J. 2009;28(3):215-219. Available at http://www.ncbi.nlm.nih.gov/pubmed/19209098.
- Foissac F, Bouazza N, Frange P, et al. Evaluation of nevirapine dosing recommendations in HIV-infected children. Br J Clin Pharmacol. 2013;76(1):137-144. Available at http://www.ncbi.nlm.nih.gov/pubmed/23278548.
- Acosta EP, Gerber JG, Adult Pharmacology Committee of the ACTG. Position paper on therapeutic drug monitoring of antiretroviral agents. AIDS Res Hum Retroviruses. 2002;18(12):825-834. Available at http://www.ncbi.nlm.nih.gov/pubmed/12201904.
- Burger DM. The role of therapeutic drug monitoring in pediatric HIV/AIDS. Ther Drug Monit. 2010;32(3):269-272. Available at http://www.ncbi.nlm.nih.gov/pubmed/20445482.