Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)
Last Updated: April 27, 2017; Last Reviewed: April 27, 2017
|Abacavir (ABC, Ziagen)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/daf/
|Pediatric Oral Solution: 20 mg/mL
Tablets: 300 mg (scored)
Fixed-Dose Combination Tablets:
|Dosing Recommendations||Selected Adverse Events|
Oral Solution (Aged ≥3 Months):
Adolescent (Weight ≥40 kg)/Adult Dose:
Adolescent (Weight ≥25 kg) and Adult Dose:
Adolescent (Weight ≥40 kg) and Adult Dose:
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%.
- 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:
- 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
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/).
Abacavir is Food and Drug Administration (FDA)-approved for use in children with HIV infection as part of the nucleoside reverse transcriptase inhibitor (NRTI) component of antiretroviral therapy.
Abacavir used either twice daily or once daily has demonstrated durable antiviral efficacy in pediatric clinical trials and is of comparable efficacy to other NRTIs in children.1-5 Abacavir in combination with lamivudine has been compared to tenofovir disoproxil fumarate with emtricitabine in several adult studies and meta-analyses with variable results.6-9
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.10
Plasma area under the drug-concentration-by-time curve (AUC) correlates with virologic efficacy of abacavir, although the association is weak.11,12 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, and changes in plasma AUC may not reflect true changes in intracellular active drug.13
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.14 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.15 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.16 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.
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 formulation.17 There is no difference in the abacavir plasma Cmax and AUC for abacavir oral solution compared to tablet formulations.18 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 pediatric subjects with HIV-1 infection aged 3 months through 12 years was evaluated in three trials (PENTA 13 [n = 14], PENTA 15 [n = 18], and ARROW [n = 36]).17,19-22 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.23
A pediatric PK model developed based on data from 69 children in the PENTA-13 and PENTA-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.24 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.
Abacavir has less of an effect on mitochondrial function than the NRTIs zidovudine, stavudine, or didanosine,1,2,25 and fewer bone and renal toxicities than tenofovir disoproxil fumarate.8,26
- Paediatric European Network for Treatment of AIDS. 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.
- 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.
- Musiime V, Kasirye P, et al. Randomised comparison of once versus twice daily abacavir and lamivudine among 669 HIV-infected children in the ARROW trial. Presented at: Conference on Retroviruses and Opportunistic Infections. 2013. Atlanta, GA.
- Adetokunboh OO, Schoonees A, Balogun TA, Wiysonge CS. Efficacy and safety of abacavir-containing combination antiretroviral therapy as first-line treatment of HIV infected children and adolescents: a systematic review and meta-analysis. BMC Infect Dis. 2015;15:469. Available at http://www.ncbi.nlm.nih.gov/pubmed/26502899.
- Mulenga V, Musiime V, Kekitiinwa A, et al. Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169-179. Available at http://www.ncbi.nlm.nih.gov/pubmed/26481928.
- Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009;361(23):2230-2240. Available at http://www.ncbi.nlm.nih.gov/pubmed/19952143.
- Smith KY, Patel P, Fine D, et al. Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS. 2009;23(12):1547-1556. Available at http://www.ncbi.nlm.nih.gov/pubmed/19542866.
- 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.
- Spaulding A, Rutherford GW, Siegfried N. Tenofovir or zidovudine in three-drug combination therapy with one nucleoside reverse transcriptase inhibitor and one non-nucleoside reverse transcriptase inhibitor for initial treatment of HIV infection in antiretroviral-naive individuals. Cochrane Database Syst Rev. 2010(10):CD008740. Available at http://www.ncbi.nlm.nih.gov/pubmed/20927777.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Abacavir (Ziagen) [package insert]. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020977s030,020978s034lbl.pdf.
- 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 https://www.ncbi.nlm.nih.gov/pubmed/22190066.
- 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.
- 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.
- 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.
- 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.
- Food and Drug Administration. FDA approved revisions to the Epivir (lamivudine) and Ziagen (abacavir sulfate) labels. 2015. Available at http://content.govdelivery.com/accounts/USFDA/bulletins/fa3e70. Accessed January 25, 2017.
- 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.
- 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.
- 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.