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Updated Pediatric ARV Guidelines

Updates to the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection were released on Thursday, November 1, 2012. Please send your comments to ContactUs@aidsinfo.nih.gov by November 15, 2012.

Corrections were made to the guideline. For a description of the changes, please see the correction notice.

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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Management of Treatment-Experienced Infants, Children, and Adolescents

Role of Therapeutic Drug Monitoring in Management of Treatment Failure

(Last updated:8/11/2011; last reviewed:11/1/2012)

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Therapeutic drug monitoring (TDM) is use of plasma drug concentration measurements as part of a strategy to optimize drug dosing to minimize toxicity and maximize treatment benefit. TDM can be considered for use in combination antiretroviral therapy because:1,2

  • Interpatient variability in antiretroviral (ARV) exposure (i.e., plasma drug concentrations) using standard recommended doses is high;
  • Low drug exposure can lead to suboptimal virologic response to therapy; and
  • High plasma concentrations can be associated with increased risk of drug toxicity.

Developmental pharmacokinetic differences contribute to greater variability and a greater frequency of suboptimal ARV exposure in pediatric patients than in adults.3 Pediatric dosing is designed to mimic adult exposure and rarely reflects the maximum tolerated ARV drug dose. Even when using dose recommendations from published pediatric guidelines, children often receive inadequate ARV doses.4

There are two main situations in which TDM may be useful in a child who is failing therapy. First, TDM can be used to rule out subtherapeutic drug levels as a cause of failure. Such inadequate drug levels could result from malabsorption, drug interactions, poor adherence, or increased drug metabolism or clearance. Second, drug levels can be used to optimize drug dosage when changing to a new regimen in a patient whose virus has reduced susceptibility to that drug.

For TDM to be useful, the relationship between ARV drug concentrations and anti-HIV effects must be clearly defined.5-7 This association is strongest with protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTIs),8 but maintaining adequate nucleoside reverse transcriptase inhibitor (NRTI) serum concentrations also has been shown to be important for maximal anti-HIV activity.9 The exposure-toxicity response relationship is less well defined for NRTI drugs but has been determined for some agents.7 Concentration-response relationships have been established with minimum plasma concentrations (Cmin or Ctrough) or area under the curve (AUC), but the optimal measure is not defined for all ARV drugs.10

Table 21 presents recommendations for the minimum target trough concentrations of PIs and NNRTIs in patients without evidence of resistance to those drugs. In ARV-experienced patients, the choice of minimum target trough concentration should be based on results of resistance testing.11-13 Although it is intrinsically difficult to demonstrate benefit of TDM using double-blind studies, limited data suggest targeted concentrations can be achieved with TDM, clinical responses can be improved with increased or modified doses, and TDM information can be helpful in decision making.8,14-18 Clinicians should consult with a pediatric HIV specialist or pharmacologist in making these decisions.

TDM is not recommended for routine use but may be considered potentially useful for patients:

  • In whom clinical response is different from that expected;
  • Who are treatment experienced and infected with virus with reduced drug susceptibility, where a comparison of the drug susceptibility of the virus and the achieved drug concentrations may be useful;
  • Who may experience potential difficulties with drug administration related to suboptimal dietary intake or malabsorption, incorrect dosing or caregiver measuring errors, or concerns surrounding adherence; and
  • Who experience drug or food interactions, including interactions resulting from alteration of drug formulations by crushing medications or mixing them with various foods and liquids.

Current limitations for pediatric ARV TDM include:

  • Prolonged time for laboratory processing in the face of potentially diminishing benefit the longer a patient is on inadequate therapy;
  • Difficulties in coordinating sample collections at appropriate times, which make determination of true Cmin or AUC difficult;
  • High intrapatient variability from single drug concentration measurements may complicate interpretation of results;19,20
  • Single trough measurements within the target range, which do not guarantee consistent adequacy of drug exposure or therapeutic success;
  • Inadequate information on safety and effectiveness of dose adjustment strategies in children and adolescents;
  • Limited availability of certified laboratories capable of assaying drug concentrations; and
  • Lack of third-party reimbursement of costs associated with TDM.

Table 21. Suggested Minimum Target Trough Concentrationsa
Click here to view the table as an image 

 Drug

Concentration (ng/mL)

 Atazanavir

150

Fosamprenavir

400
(measured as amprenavir concentration)

 Indinavir

100

 Lopinavir

1,000

Nelfinavir (measurable active [M8] metabolite)

800

Saquinavir

100-250

Efavirenz

1,000

Nevirapine

3,000

Recommendations applicable only to treatment-experienced persons who have resistant HIV-1 strains

Maraviroc

>50

Tiprinavir

20,500
a Reprinted from: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf.

References

  1. Fraaij PL, Rakhmanina N, Burger DM, de Groot R. Therapeutic drug monitoring in children with HIV/AIDS. Ther Drug Monit. Apr 2004;26(2):122-126. Available at http://www.ncbi.nlm.nih.gov/pubmed/15228151.
  2. 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. Jun 2010;32(3):273-281. Available at http://www.ncbi.nlm.nih.gov/pubmed/20445485.
  3. 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. Sep 18 2003;349(12):1157-1167. Available at http://www.ncbi.nlm.nih.gov/pubmed/13679531.
  4. Menson EN, Walker AS, Sharland M, et al. Underdosing of antiretrovirals in UK and Irish children with HIV as an example of problems in prescribing medicines to children, 1997-2005: cohort study. BMJ. May 20 2006;332(7551):1183-1187. Available at http://www.ncbi.nlm.nih.gov/pubmed/16709991.
  5. Acosta EP, Gerber JG, Adult Pharmacology Committee of the ACTG. Position paper on therapeutic drug monitoring of antiretroviral agents. AIDS Res Hum Retroviruses. Aug 10 2002;18(12):825-834. Available at http://www.ncbi.nlm.nih.gov/pubmed/12201904.
  6. Anderson PL, Fletcher CV. Updated clinical pharmacologic considerations for HIV-1 protease inhibitors. Curr HIV/AIDS Rep. Apr 2004;1(1):33-39. Available at http://www.ncbi.nlm.nih.gov/pubmed/16091221.
  7. Morse GD, Catanzaro LM, Acosta EP. Clinical pharmacodynamics of HIV-1 protease inhibitors: use of inhibitory quotients to optimise pharmacotherapy. Lancet Infect Dis. Apr 2006;6(4):215-225. Available at http://www.ncbi.nlm.nih.gov/pubmed/16554246.
  8. Burger D, Hugen P, Reiss P, et al. Therapeutic drug monitoring of nelfinavir and indinavir in treatment-naive HIV-1-infected individuals. AIDS. May 23 2003;17(8):1157-1165. Available at http://www.ncbi.nlm.nih.gov/pubmed/12819517.
  9. Fletcher CV, Acosta EP, Henry K, et al. Concentration-controlled zidovudine therapy. Clin Pharmacol Ther. Sep 1998;64(3):331-338. Available at http://www.ncbi.nlm.nih.gov/pubmed/9757157.
  10. Back D, Gatti G, Fletcher C, et al. Therapeutic drug monitoring in HIV infection: current status and future directions. AIDS. Mar 2002;16 Suppl 1:S5-37. Available at http://www.ncbi.nlm.nih.gov/pubmed/12035820.
  11. Acosta EP, King JR. Methods for integration of pharmacokinetic and phenotypic information in the treatment of infection with human immunodeficiency virus. Clin Infect Dis. Feb 1 2003;36(3):373-377. Available at http://www.ncbi.nlm.nih.gov/pubmed/12539082.
  12. Ellner PD, Neu HC. The inhibitory quotient. A method for interpreting minimum inhibitory concentration data. JAMA. Oct 2 1981;246(14):1575-1578. Available at http://www.ncbi.nlm.nih.gov/pubmed/7277631.
  13. Hsu A, Isaacson J, Brun S, et al. Pharmacokinetic-pharmacodynamic analysis of lopinavir-ritonavir in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in extensively pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. Jan 2003;47(1):350-359. Available at http://www.ncbi.nlm.nih.gov/pubmed/12499212.
  14. Best B, Witt M, Goicoechea M, et al. Improved antiretroviral exposure with therapeutic drug monitoring. Paper presented at: 13th Conference on Retroviruses and Opportunistic Infections; February 5–8, 2006; Denver, CO.
  15. Bossi P, Peytavin G, Ait-Mohand H, et al. GENOPHAR: A randomized study of plasma drug measurements in association with genotypic resistance testing and expert advice to optimize therapy in patients failing antiretroviral therapy. HIV Med. Sep 2004;5(5):352-359. Available at http://www.ncbi.nlm.nih.gov/pubmed/15369510.
  16. Clevenbergh P, Garraffo R, Durant J, Dellamonica P. PharmAdapt: a randomized prospective study to evaluate the benefit of therapeutic monitoring of protease inhibitors: 12 week results. AIDS. Nov 22 2002;16(17):2311-2315. Available at http://www.ncbi.nlm.nih.gov/pubmed/12441803.
  17. de Requena DG, Nunez M, Gallego O, Jimenez-Nacher I, Gonzalez-Lahoz J, Soriano V. Does an increase in nevirapine plasma levels cause complete virologic suppression in patients experiencing early virologic failure? HIV Clin Trials. Nov-Dec 2002;3(6):463-467. Available at http://www.ncbi.nlm.nih.gov/pubmed/12501129.
  18. Fletcher CV, Anderson PL, Kakuda TN, et al. Concentration-controlled compared with conventional antiretroviral therapy for HIV infection. AIDS. Mar 8 2002;16(4):551-560. Available at http://www.ncbi.nlm.nih.gov/pubmed/11872998.
  19. Haas DW. Can responses to antiretroviral therapy be improved by therapeutic drug monitoring? Clin Infect Dis. Apr 15 2006;42(8):1197-1199. Available at http://www.ncbi.nlm.nih.gov/pubmed/16575742.
  20. Nettles RE, Kieffer TL, Parsons T, et al. Marked intraindividual variability in antiretroviral concentrations may limit the utility of therapeutic drug monitoring. Clin Infect Dis.Apr 15 2006;42(8):1189-1196. Available at http://www.ncbi.nlm.nih.gov/pubmed/16575741.