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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)

Abacavir

(Last updated: March 1, 2016; last reviewed: March 1, 2016)

Abacavir (ABC, Ziagen)
Abacavir (ABC, Ziagen)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations
Pediatric Oral Solution: 20 mg/mL
Tablets: 300 mg (scored)
Fixed-Dose Combination Tablets:
  • [Epzicom] Abacavir 600 mg plus lamivudine 300 mg
  • [Trizivir] Abacavir 300 mg plus lamivudine 150 mg plus zidovudine 300 mg
  • [Triumeq] Abacavir 600 mg plus dolutegravir 50 mg plus lamivudine 300 mg
Generic Formulations:
  • Abacavir sulfate 300 mg tablets
  • Fixed-dose combination tablets of abacavir 300 mg plus lamivudine 150 mg plus zidovudine 300 mg
Dosing Recommendations Selected Adverse Events
Neonate/Infant Dose:
  • Not approved for infants aged <3 months.
Pediatric Dose:
Oral Solution (Aged ≥3 Months):
  • 8 mg/kg (maximum 300 mg per dose) twice daily or 16 mg/kg once daily (maximum 600 mg per dose) (see text below)
  • In infants and young children being treated with liquid formulations of abacavir, initiation with once daily abacavir is not generally recommended. In clinically stable patients with undetectable viral load and stable CD4 T lymphocyte (CD4) cell counts for more than 6 months (24 weeks) on abacavir twice daily, dose can be changed from twice daily to once daily (see text below).
Weight Band Dosing (Weighing ≥14 kg)
Scored 300-mg tablet
Weight (kg)
Twice Daily AM Dose Twice Daily PM Dose Once Daily Dose
14 to <20 kg ½ tablet
(150 mg)
½ tablet
(150 mg)
1 tablet
(300 mg)
≥20 to <25 kg ½ tablet
(150 mg)
1 tablet
(300 mg)
1½ tablets
(450 mg)
≥25 kg 1 tablet
(300 mg)
1 tablet
(300 mg)
2 tablets
(600 mg)

  • In patients who can be treated with pill formulations, therapy can be initiated with once daily administration. If therapy was initiated with twice daily liquid abacavir then it can be changed from twice daily to once daily in clinically stable patients with undetectable viral load and stable CD4 cell counts (without decline) for more than 6 months (24 weeks) (see text below).
Adolescent (Weighing ≥25 kg) and Adult Dose:
  • 300 mg twice daily or 600 mg once daily.
[Trizivir] Abacavir plus Lamivudine plus Zidovudine
Adolescent (Weight ≥40 kg)/Adult Dose:
  • One tablet twice daily.
[Epzicom] Abacavir plus Lamivudine
Adolescent (Weighing ≥25 kg) and Adult Dose:
  • One tablet once daily.
[Triumeq] Abacavir plus Dolutegravir plus Lamivudine
Adolescent (Weighing ≥40 kg) and Adult Dose:
  • One tablet once daily.
  • Hypersensitivity reactions can be fatal. Hypersensitivity reactions usually occur during the first few weeks of starting therapy. Symptoms may include fever, rash, nausea, vomiting, malaise or fatigue, loss of appetite, and respiratory symptoms (e.g., cough and shortness of breath).
  • Several observational cohort studies suggest increased risk of myocardial infarction in adults with recent or current use of abacavir; however, other studies have not substantiated this finding, and there are no data in children.
Special Instructions
  • Test patients for the HLA-B*5701 allele before starting therapy to predict risk of HSR. Patients positive for the HLA-B*5701 allele should not be given abacavir. Patients with no prior HLA-B*5701 testing who are tolerating abacavir do not need to be tested.
  • Warn patients and parents about risk of serious, potentially fatal hypersensitivity reactions. Occurrence of hypersensitivity reactions requires immediate and permanent discontinuation of abacavir. Do not re-challenge.
  • Abacavir can be given without regard to food. Oral solution does not require refrigeration.
Metabolism/Elimination
  • Systemically metabolized by alcohol dehydrogenase and glucuronyltransferase.
  • Intracellularly metabolized to carbovir triphosphate (CBV-TP).
  • Active metabolite is 82% renally excreted.
  • Abacavir requires dosage adjustment in hepatic insufficiency.
  • Do not use fixed-dose combinations such as Trizivir, Epzicom, and Triumeq (or the fixed-dose combination’s generic equivalents), in patients with impaired hepatic function because the dose of abacavir cannot be adjusted.
  • Do not use Trizivir, Epzicom, and Triumeq (or the fixed-dose combination’s generic equivalents) in patients with creatinine clearance (CrCl) <50 mL/min and patients on dialysis (because of the fixed dose of lamivudine).

Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and http://www.hiv-druginteractions.org/)

  • Abacavir does not inhibit, nor is it metabolized by, hepatic cytochrome P (CYP) 450 enzymes. Therefore, it does not cause changes in clearance of agents metabolized through these pathways, such as protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (see more information in Drug Interaction section under Pediatric Use).
  • Through interference with alcohol dehydrogenase and glucuronyltransferase, 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. HSR to abacavir is a multi-organ clinical syndrome usually characterized by rash or signs or symptoms in two or more of the following groups:
    • Fever
    • Constitutional, including malaise, fatigue, or achiness
    • Gastrointestinal, including nausea, vomiting, diarrhea, or abdominal pain
    • Respiratory, including dyspnea, cough, or pharyngitis
    • Laboratory and radiologic abnormalities include elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, lymphopenia, and pulmonary infiltrates. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have also been reported. Pancreatitis can occur. This reaction generally occurs in the first 6 weeks of therapy, but has also been reported after a single dose. If an HSR is suspected, abacavir should be stopped immediately and not restarted—hypotension and death may occur upon re-challenge. The risk of abacavir HSR is associated with the presence of HLA-B*5701 allele; it is greatly reduced by not using abacavir in those who test positive for the HLA-B*5701 allele.
  • Rare: Increased liver enzymes, elevated blood glucose, elevated triglycerides, and possible increased risk of myocardial infarction (in observational studies in adults). Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Pancreatitis can occur.
  • Rare: Drug Reaction (or Rash) with Eosinophilia and Systemic Symptoms (DRESS) Syndrome

Resistance

The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://iasusa.org/sites/default/files/tam/october_november_2015.pdf#page=10) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/DR/).

Pediatric Use

Approval
Abacavir is Food and Drug Administration (FDA)-approved for use in HIV-infected children as part of the nucleoside reverse transcriptase inhibitor (NRTI) component of antiretroviral therapy (ART).

Efficacy
Abacavir used either twice daily or once daily has demonstrated durable antiviral efficacy in pediatric clinical trials.1-3 A retrospective analysis of observational data from 2 cohorts of African children aged <16 years suggested lower levels of viral suppression in children receiving first-line abacavir/lamivudine-based ART compared to stavudine/lamivudine-based ART; however, observational data may have multiple confounders and further data collection and analysis are needed before conclusions can be drawn (see What to Start).4,5

Pharmacokinetics

Pharmacokinetics in Children
Pharmacokinetic (PK) studies of abacavir in children aged <12 years have demonstrated that children have more rapid clearance of abacavir than adults. Metabolic clearance of abacavir in adolescents and young adults (aged 13–25 years) is slower than that observed in younger children and approximates clearance seen in older adults.6

Exposure-Response Relationship
Plasma area under the drug-concentration-by-time curve (AUC) correlates with virologic efficacy of abacavir, although the association is weak.7,8 The active form of abacavir is the intracellular metabolite carbovir triphosphate (CBV-TP). Measurement of intracellular CBV-TP is more difficult than measurement of plasma AUC, so the abacavir plasma AUC is frequently considered 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.9 Intracellular CBV-TP concentrations are affected by gender and have been reported to be higher in females than in males.9-11 This effect of gender and the PIs (see Drug Interactions section below) on abacavir PK further complicates linkage of clinically available plasma abacavir concentrations with more difficult to obtain—but pharmacodynamically more important—intracellular CBV-TP concentrations.

Drug Interactions
Abacavir plasma AUC has been reported to be decreased by 17% and 32% with concurrent use of the PIs atazanavir/ritonavir and lopinavir/ritonavir (LPV/r), respectively.12 In a study comparing PK parameters of abacavir in combination with either LPV/r or nevirapine, abacavir plasma AUC was decreased 40% by concurrent use of LPV/r; however, the CBV-TP concentrations appeared to be increased in the LPV/r cohort.11 When combined with darunavir/ritonavir, abacavir plasma AUC and trough concentrations were decreased by 27% and 38%, respectively; the CBV-TP AUC and trough concentrations were decreased by 12% and 32%, respectively.13 The mechanism and the clinical significance of these drug interactions with the PIs are unknown and need to be evaluated. No dose adjustments for abacavir or PIs are currently recommended.

Dosing

Appropriate Total Daily Dose
The initially recommended abacavir dose for pediatric use was 8 mg/kg/dose twice daily, or 16 mg/kg total daily dose. A 2015 FDA review suggested that a total daily dose of abacavir of 600 mg could be safely used in a 25-kg person (i.e., 24 mg/kg/day, a 50% increase from the previously recommended dose). The weight band dosing table recommends total daily doses as high as 21.5 to 22.5 mg/kg/day when treating with pill formulations.14 There is no difference in the abacavir plasma Cmax and AUC for abacavir oral solution compared to tablet formulations.15 Doses of liquid abacavir similar to those used for weight band dosing with tablets might be considered in some situations, especially in rapidly growing younger children.

Frequency of Administration
New PK data suggest that once-daily dosing of abacavir in children is feasible. In children who can be treated with pill formulations, initiation of therapy with once-daily dosing of abacavir (at a dose of 16 mg/kg/dose [maximum of 600 mg] once daily) is recommended, but in infants and young children initiating therapy with liquid formulations of abacavir, twice-daily dosing is recommended with consideration of a switch to once-daily dosing after 6 months (24 weeks) when viral load is undetectable and CD4 cell count is stable (without decline). This recommendation is based on the data presented below.

The PK of abacavir dosed once daily in HIV 1-infected pediatric subjects aged 3 months through 12 years was evaluated in three trials (PENTA 13 [n = 14], PENTA 15 [n = 18], and ARROW [n = 36]).14,16-19 All three trials were two-period, crossover, open-label PK trials of twice- versus once-daily dosing of abacavir and lamivudine. For the oral solution as well as the tablet formulation, these three trials demonstrated that once-daily dosing provides comparable AUC0-24 to twice-daily dosing of abacavir at the same total daily dose. The mean Cmax was approximately 1.6- to 2.3-fold higher with abacavir once-daily dosing compared with twice-daily dosing.20

A pediatric PK model developed based on data from 69 children in the PENTA-13 and -15 trials and the ARROW study predicted that steady state peak (Cmax) and AUC0-12 abacavir concentrations on standard twice-daily dosing were lower in toddlers, and infants aged 0.4 to 2.8 years when compared with children aged 3.6 to 12.8 years. Model-based predictions also showed that equivalent systemic plasma abacavir exposure was achieved after once- or twice-daily dosing regimens in infants, toddlers and children up to age 12 years.21 The pediatric studies referenced above enrolled only patients who had low viral loads and were clinically stable on twice-daily abacavir before changing to once-daily dosing. Efficacy data from 48-week follow-up in the ARROW trial demonstrated clinical non-inferiority of once-daily (336 children) versus twice-daily abacavir (333 children) in combination with a once- or twice-daily lamivudine-based regimen.3

No clinical trials have been conducted involving children who initiated therapy with once-daily dosing of abacavir solution.

Toxicity

Abacavir has less of an effect on mitochondrial function than the nucleoside reverse-transcriptase inhibitors zidovudine, stavudine, or didanosine,1,2,22 and fewer bone and renal toxicities than tenofovir disoproxil fumarate.23,24

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. 2007;21(8):947-955. Available at http://www.ncbi.nlm.nih.gov/pubmed/17457088.
  3. Musiime V, Kasirye P, al e. Randomised comparison of once versus twice daily abacavir and lamivudine among 669 HIV-infected children in the ARROW trial. Conference on Retroviruses and Opportunistic Infections. 2013. Atlanta, GA.
  4. Technau KG, Lazarus E, Kuhn L, et al. Poor early virologic performance and durability of abacavir-based first-line regimens for HIV-infected children. Pediatr Infect Dis J. 2013;32(8):851-855. Available at http://www.ncbi.nlm.nih.gov/pubmed/23860481.
  5. Technau KG, Schomaker M, Kuhn L, et al. Virologic response in children treated with abacavir-compared with stavudine-based antiretroviral treatment: a South African multi-cohort analysis. Pediatr Infect Dis J. 2014;33(6):617-622. Available at http://www.ncbi.nlm.nih.gov/pubmed/24378944.
  6. Sleasman JW, Robbins BL, Cross SJ, et al. Abacavir pharmacokinetics during chronic therapy in HIV-1-infected adolescents and young adults. Clin Pharmacol Ther. 2009;85(4):394-401. Available at http://www.ncbi.nlm.nih.gov/pubmed/19118380.
  7. 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. 2000;44(8):2061-2067. Available at http://www.ncbi.nlm.nih.gov/pubmed/10898676.
  8. 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. 2000;44(8):2052-2060. Available at http://www.ncbi.nlm.nih.gov/pubmed/10898675.
  9. 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. 2009;53(4):1532-1538. Available at http://www.ncbi.nlm.nih.gov/pubmed/19188387.
  10. Harris M, Back D, Kewn S, Jutha S, Marina R, Montaner JS. Intracellular carbovir triphosphate levels in patients taking abacavir once a day. AIDS. 2002;16(8):1196-1197. Available at http://www.ncbi.nlm.nih.gov/pubmed/12004286.
  11. 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. 2009;53(5):1937-1943. Available at http://www.ncbi.nlm.nih.gov/pubmed/19273671.
  12. 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.
  13. Jackson A, Moyle G, Dickinson L, et al. Pharmacokinetics of abacavir and its anabolite carbovir triphosphate without and with darunavir/ritonavir or raltegravir in HIV-infected subjects. Antivir Ther. 2012;17(1):19-24. Available at http://www.ncbi.nlm.nih.gov/pubmed/22267465.
  14. Abacavir sulfate (Ziagen) [package insert]. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020977s028,020978s032lbl.pdf. Accessed January 29, 2016.
  15. Kasirye P, Kendall L, Adkison KK, et al. Pharmacokinetics of antiretroviral drug varies with formulation in the target population of children with HIV-1. Clin Pharmacol Ther. 2012;91(2):272-280. Available at http://www.ncbi.nlm.nih.gov/pubmed/22190066.
  16. 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. 2006;25(6):533-537. Available at http://www.ncbi.nlm.nih.gov/pubmed/16732152.
  17. 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.
  18. Paediatric European Network for Treatment of Aids. 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/pubmed/20516550.
  19. 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.
  20. Lamivudine and abacavir sulfate [FDA-approved revisions to package insert]. Food and Drug Administration. 2015. Available at: http://content.govdelivery.com/accounts/USFDA/bulletins/fa3e70. 2015. Accessed January 29, 2016.
  21. Zhao W, Piana C, Danhof M, Burger D, Pasqua OD, Jacqz-Aigrain E. Population pharmacokinetics of abacavir in infants, toddlers and children. Br J Clin Pharmacol. 2012. Available at http://www.ncbi.nlm.nih.gov/pubmed/23126277.
  22. Moyle GJ, Sabin CA, Cartledge J, et al. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS. 2006;20(16):2043-2050. Available at http://www.ncbi.nlm.nih.gov/pubmed/17053350.
  23. Post FA, Moyle GJ, Stellbrink HJ, et al. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine, administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week results from the ASSERT study. J Acquir Immune Defic Syndr. 2010;55(1):49-57. Available at http://www.ncbi.nlm.nih.gov/pubmed/20431394.
  24. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011;203(12):1791-1801. Available at http://www.ncbi.nlm.nih.gov/pubmed/21606537.

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