• What's New in the Guidelines
• Guidelines Panel Members
• Financial Disclosure
• Introduction
• Identification of Perinatal HIV Exposure
• Diagnosis of HIV Infection in Infants and Children
• Laboratory Monitoring of Pediatric HIV Infection Prior to Therapy Initiation
• Treatment Recommendations
• When to Initiate Therapy in Antiretroviral-Naive Children
• What Drugs to Start: Initial Combination Therapy for Antiretroviral Treatment-Naive Children
  • General Considerations
  • Regimens Recommended for Initial Therapy of Antiretroviral-Naive Children
• Monitoring of Children on Antiretroviral Therapy
• Specific Issues in Antiretroviral Therapy for HIV-Infected Adolescents
• Adherence to Antiretroviral Therapy in HIV-Infected Children and Adolescents
• Management of Medication Toxicity or Intolerance
  • CNS Toxicity
  • Dyslipidemia
  • Gastrointestinal Effects
  • Hematologic Effects
  • Hepatic Events
  • Insulin Resistance, Asymptomatic Hyperglycemia, Diabetes Mellitus
  • Lactic Acidosis
  • Lipodystrophy, Lipohypertrophy, Lipoatrophy
  • Nephrotoxic Effects
  • Osteopenia, Osteoporosis, Osteonecrosis
  • Peripheral Nervous System Toxicity
  • Skin Rash, SJS/EM/TEN, HSR
• Management of Treatment-Experienced Infants, Children, and Adolescents
  • Overview
  • Assessment of Patients with Virologic Failure of Antiretroviral Treatment
  • Approach to the Management of Virologic Failure of Antiretroviral Treatment
  • Choice of Next Antiretroviral Regimen for Virologic Treatment Failure with Evidence of Drug Resistance
  • The Use of Antiretroviral Agents Not Approved for Use in Children
  • Role of Therapeutic Drug Monitoring in Management of Treatment Failure
  • Discontinuation or Interruption of Therapy
• Antiretroviral Drug-Resistance Testing
• Conclusion
• Appendix A: Pediatric Antiretroviral Drug Information
  • Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)
    • Abacavir
    • Didanosine
    • Emtricitabine
    • Lamivudine
    • Stavudine
    • Tenofovir
    • Zidovudine
  • Non-Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)
    • Efavirenz
    • Etravirine
    • Nevirapine
    • Rilpivirine
  • Protease Inhibitors (PIs)
    • Atazanavir
    • Darunavir
    • Fosamprenavir
    • Indinavir
    • Lopinavir/Ritonavir
    • Nelfinavir
    • Ritonavir
    • Saquinavir
    • Tiprinavir
  • Entry and Fusion Inhibitors
    • Enfuvirtide
    • Maraviroc
  • Integrase Inhibitors
    • Raltegravir
    • Elvitegravir
• Appendix B: Acronyms

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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents):

• Abacavir does not inhibit, nor is it metabolized by, hepatic cytochrome P (CYP) 450 enzymes. Thus, it should not cause changes in clearance of agents metabolized through these pathways, such as protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors.
• Abacavir is metabolized by alcohol dehydrogenase and glucuronyl transferase. Alcohol increases abacavir levels by 41%.

Major Toxicities:

• More common: Nausea, vomiting, fever, headache, diarrhea, rash, and anorexia.
• Less common (more severe): Serious and sometimes fatal hypersensitivity reactions (HSRs) observed in approximately 5% of adults and children (rate varies by race/ethnicity) receiving abacavir. Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by rash or signs or symptoms in two or more of the following groups: (1) fever; (2) constitutional, including malaise, fatigue, or achiness; (3) gastrointestinal, including nausea, vomiting, diarrhea, or abdominal pain; or (4) respiratory, including dyspnea, cough, or pharnygitis. Laboratory and imaging abnormalities include elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, lymphopenia, and pulmonary infiltrates. This reaction generally occurs in the first 6 weeks of therapy and has occurred after a single dose. If an HSR is suspected, abacavir should be stopped and not restarted because hypotension and death have occurred upon re-challenge. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Pancreatitis can occur.
• Rare: Increased liver enzymes, elevated blood glucose, elevated triglycerides, and possible increased risk of myocardial infarction (in observational studies in adults).

Resistance: The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://www.iasusa.org/resistance_mutations/index.html) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/pages/GRIP/ABC.html).

Pediatric Use: Abacavir is Food and Drug Administration (FDA) approved for use in HIV-infected children as one of the drugs for part of the nucleoside reverse transcriptase inhibitor (NRTI) component of antiretroviral therapy (ART). The liquid formulation of abacavir is more palatable than zidovudine; it has less of an effect on mitochondrial function than zidovudine, stavudine, or didanosine; and it has more durable antiviral effectiveness in pediatric trials.^1,2 The risk of abacavir hypersensitivity syndrome, the major toxicity limiting abacavir’s use, is greatly reduced by testing patients for HLA-B*5701 and by not using abacavir in those who test positive for the HLA-B*5701 allele.

Pharmacokinetic (PK) studies of abacavir in children aged <12 years have demonstrated that children have more rapid clearance of abacavir than adults and that pediatric doses approximately twice the directly scaled adult dose are necessary to achieve similar systemic exposure.^3,4 Metabolic clearance of abacavir in adolescents and young adults (ages 13–25 years) is slower than that observed in younger children and approximates clearance seen in older adults.⁵

Plasma area under the drug concentration by time curve (AUC) correlates with virologic efficacy of abacavir, although the association is weak.^6,7 Intracellular concentrations of NRTIs are most strongly associated with antiviral effectiveness, and the active form of abacavir is the intracellular metabolite carbovir triphosphate.^8,9 Measurement of intracellular carbovir triphosphate is more difficult than measurement of plasma AUC, so the abacavir plasma AUC is often taken as a proxy measurement for intracellular concentrations. However, this relationship is not sufficiently strong that changes in plasma AUC can be assumed to reflect true changes in intracellular active drug. For example, although overall intracellular carbovir triphosphate was correlated with abacavir plasma AUC, this relationship was not found when gender was considered in PK modeling¹⁰ because carbovir triphosphate concentrations were higher in females than in males.^10-12 This effect of gender on intracellular triphosphates has also been found with zidovudine and lamivudine.^8,13

In studies in adults, abacavir plasma AUC is decreased 17% by concurrent use of atazanavir/ritonavir and decreased 32% by concurrent use of lopinavir/ritonavir.¹⁴ In a study comparing PK parameters of abacavir in combination with either lopinavir/ritonavir or nevirapine, abacavir plasma AUC was decreased 40% by concurrent use of lopinavir/ritonavir, but the carbovir triphosphate concentration seemed to increase in the lopinavir/ritonavir group.¹²

These effects of gender and concurrent PI use add to the complexity of linking readily available plasma abacavir AUC with more difficult to obtain but pharmacodynamically more important intracellular carbovir triphosphate concentrations. These effects also need to be kept in mind when considering data supporting the use of once-daily abacavir in children (presented in the table below).

Abacavir 600 mg once daily is standard for use in adults, but once-daily use for children is still controversial. The PENTA-13 crossover trial studied abacavir 16 mg/kg once daily versus 8 mg/kg twice daily in 24 children aged 2 to 13 years who had undetectable or low, stable viral loads at the time of changing from twice-daily to once-daily abacavir. This study showed equivalent AUC_0-24 for both drugs and improved acceptability in the once-daily dosing arm.^15,16 However, trough concentrations were lower in younger children (aged 2–6 years) receiving the once-daily regimen.¹⁶ The PENTA-15 crossover trial studied 18 children aged 3 to 36 months, again comparing abacavir 16 mg/kg once daily versus 8 mg/kg twice daily in children with viral loads <400 copies/mL or “stable” on twice-daily abacavir at baseline. AUC_0-24 and clearance were similar on the once- and twice-daily regimens. After the change from twice-daily to once-daily abacavir, viral load remained <400 copies/mL in 16 of 18 participants through 48 weeks of monitoring. A study of 41 children aged 3 to 6 years (median age 7.6 years) in Uganda who were stable on twice-daily abacavir also showed equivalent AUC_0-24 and good clinical outcome (disease stage and CD4 T lymphocyte (CD4 cell) count) after the switch to once-daily abacavir, with median follow-up of 1.15 years. Viral load testing was not done.¹⁸

Abacavir Steady State Pharmacokinetics When Dosed Once Daily or Twice Daily
Click here to view this table as an image

Key to Abbreviations: AUC = area under the curve, PI = protease inhibitor

Data are medians except as noted.
^a mean
^b geometric mean
^c total daily dose in mg/kg (divided doses were given but sometimes in unequal amounts morning and evening)
^d total dose in mg
^e interquartile range
^f clearance in mL/min/kg
^g AUC in fmol/10⁶ cells

No clinical trials exist involving children who initiated ART with once-daily dosing of abacavir. All three pediatric studies described in the table above enrolled only patients who had low viral loads or were “clinically stable” on twice-daily abacavir before changing to once-daily dosing. Therefore, the Panel suggests that in clinically stable patients with undetectable viral loads and stable CD4 cell counts, switching to once-daily dosing of abacavir (at a dose of 16 to 20 mg/kg/dose to maximum of 600 mg once daily) can be considered.

References

1. Paediatric European Network for Treatment of AIDS (PENTA). Comparison of dual nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with HIV-1 who have not previously been treated: the PENTA 5 randomised trial. Lancet. 2002;359(9308):733-740. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11888583&query_hl=42.
2. Green H, Gibb DM, Walker AS, et al. Lamivudine/abacavir maintains virological superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in children. AIDS. May 11 2007;21(8):947-955. Available at http://www.ncbi.nlm.nih.gov/pubmed/17457088.
3. Hughes W, McDowell JA, Shenep J, et al. Safety and single-dose pharmacokinetics of abacavir (1592U89) in human immunodeficiency virus type 1-infected children. Antimicrob Agents Chemother. Mar 1999;43(3):609-615. Available at http://www.ncbi.nlm.nih.gov/pubmed/10049275.
4. Cross SJ, Rodman JH, Lindsey JC, et al. Abacavir and metabolite pharmacokinetics in HIV-1-infected children and adolescents. J Acquir Immune Defic Syndr. May 1 2009;51(1):54-59. Available at http://www.ncbi.nlm.nih.gov/pubmed/19282779.
5. Sleasman JW, Robbins BL, Cross SJ, et al. Abacavir pharmacokinetics during chronic therapy in HIV-1-infected adolescents and young adults. Clin Pharmacol Ther. Apr 2009;85(4):394-401. Available at http://www.ncbi.nlm.nih.gov/pubmed/19118380.
6. McDowell JA, Lou Y, Symonds WS, Stein DS. Multiple-dose pharmacokinetics and pharmacodynamics of abacavir alone and in combination with zidovudine in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. Aug 2000;44(8):2061-2067. Available at http://www.ncbi.nlm.nih.gov/pubmed/10898676.
7. Weller S, Radomski KM, Lou Y, Stein DS. Population pharmacokinetics and pharmacodynamic modeling of abacavir (1592U89) from a dose-ranging, double-blind, randomized monotherapy trial with human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother. Aug 2000;44(8):2052-2060. Available at http://www.ncbi.nlm.nih.gov/pubmed/10898675.
8. Anderson PL, Kakuda TN, Kawle S, Fletcher CV. Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals. AIDS. Oct 17 2003;17(15):2159-2168. Available at http://www.ncbi.nlm.nih.gov/pubmed/14523272.
9. Fletcher CV, Kawle SP, Kakuda TN, et al. Zidovudine triphosphate and lamivudine triphosphate concentration-response relationships in HIV-infected persons. AIDS. Sep 29 2000;14(14):2137-2144. Available at http://www.ncbi.nlm.nih.gov/pubmed/11061655.
10. Moyle G, Boffito M, Fletcher C, et al. Steady-state pharmacokinetics of abacavir in plasma and intracellular carbovir triphosphate following administration of abacavir at 600 milligrams once daily and 300 milligrams twice daily in human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother. Apr 2009;53(4):1532-1538. Available at http://www.ncbi.nlm.nih.gov/pubmed/19188387.
11. Harris M, Back D, Kewn S, Jutha S, Marina R, Montaner JS. Intracellular carbovir triphosphate levels in patients taking abacavir once a day. AIDS. May 24 2002;16(8):1196-1197. Available at http://www.ncbi.nlm.nih.gov/pubmed/12004286.
12. Pruvost A, Negredo E, Theodoro F, et al. Pilot pharmacokinetic study of human immunodeficiency virus-infected patients receiving tenofovir disoproxil fumarate (TDF): investigation of systemic and intracellular interactions between TDF and abacavir, lamivudine, or lopinavir-ritonavir. Antimicrob Agents Chemother. May 2009;53(5):1937-1943. Available at http://www.ncbi.nlm.nih.gov/pubmed/19273671.
13. Stretcher BN, Pesce AJ, Frame PT, Stein DS. Pharmacokinetics of zidovudine phosphorylation in peripheral blood mononuclear cells from patients infected with human immunodeficiency virus. Antimicrob Agents Chemother. Jul 1994;38(7):1541-1547. Available at http://www.ncbi.nlm.nih.gov/pubmed/7979286.
14. Waters LJ, Moyle G, Bonora S, et al. Abacavir plasma pharmacokinetics in the absence and presence of atazanavir/ritonavir or lopinavir/ritonavir and vice versa in HIV-infected patients. Antivir Ther. 2007;12(5):825-830. Available at http://www.ncbi.nlm.nih.gov/pubmed/17713166.
15. LePrevost M, Green H, Flynn J, et al. Adherence and acceptability of once daily Lamivudine and abacavir in human immunodeficiency virus type-1 infected children. Pediatr Infect Dis J. Jun 2006;25(6):533-537. Available at http://www.ncbi.nlm.nih.gov/pubmed/16732152.
16. Bergshoeff A, Burger D, Verweij C, et al. Plasma pharmacokinetics of once- versus twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-infected children (PENTA-13). Antivir Ther. 2005;10(2):239-246. Available at http://www.ncbi.nlm.nih.gov/pubmed/15865218.
17. Pharmacokinetic study of once-daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3–<36 months. Antivir Ther. 2010;15(3):297-305. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20516550.
18. Musiime V, Kendall L, Bakeera-Kitaka S, et al. Pharmacokinetics and acceptability of once- versus twice-daily lamivudine and abacavir in HIV type-1-infected Ugandan children in the ARROW Trial. Antivir Ther. 2010;15(8):1115-1124. Available at http://www.ncbi.nlm.nih.gov/pubmed/21149918.