Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)
Last Updated: May 22, 2018; Last Reviewed: May 22, 2018
|Abacavir (ABC, Ziagen)
For additional information see Drugs@FDA: https://www.accessdata.fda.gov/scripts/cder/daf/
|Tablets: 300 mg (scored)
Pediatric Oral Solution: 20 mg/mL
Fixed-Dose Combination Tablets:
|Dosing Recommendations||Selected Adverse Events|
Oral Solution (Aged ≥3 Months):
Adolescent (Weighing ≥40 kg) and Adult Dose:
Adolescent (Weighing ≥25 kg) and Adult Dose:
Adolescent (Weighing ≥40 kg) and Adult Dose:
- Abacavir does not inhibit, nor is it metabolized by, hepatic cytochrome P (CYP) 450 enzymes. Therefore, it does not cause significant changes in clearance of agents metabolized through these pathways, such as protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors. Abacavir plasma area under the drug-concentration-by-time curve (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.1 Another study reported decrease in plasma abacavir AUC by 40% with concurrent use of LPV/r; however, the intracellular metabolite carbovir triphosphate concentrations appeared to be increased with LPV/r exposure.2 Co-administration with darunavir/ritonavir has produced a decrease in abacavir plasma AUC and trough concentrations by 27% and 38%, respectively; the carbovir triphosphate AUC and trough concentrations were also decreased by 12% and 32%, respectively.3 The mechanism and the clinical significance of these drug interactions with the PIs are unknown. No dose adjustments for abacavir or PIs are currently recommended.
- Through interference with alcohol dehydrogenase and glucuronyltransferase, alcohol exposure (0.7 g per kg ethanol, which is equivalent to five alcoholic drinks) has been shown to increase abacavir AUC plasma exposure by 41% in adult men with HIV receiving 600 mg of abacavir daily.4
- Abacavir oral solution contains sorbitol, which decreased exposure of concurrently administered lamivudine solution in adults.5
- 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, including 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 a 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
- Rare: 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.
Abacavir is Food and Drug Administration (FDA)-approved for use in children aged 3 months and older 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.6-10 Abacavir in combination with lamivudine has been compared to tenofovir disoproxil fumarate (TDF) with emtricitabine in several adult studies and meta-analyses with variable results.11-14
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.15
The PK of abacavir dosed once daily in pediatric subjects (aged 3 months through 12 years ) with HIV-1 infection was evaluated in three crossover, open-label PK trials of twice- versus once-daily dosing of abacavir and lamivudine (PENTA 13 [n = 14], PENTA 15 [n = 18], and ARROW [n = 36]).4,16-19 PK abacavir modeling based on the data from these three pediatric trials predicted overall equivalent systemic plasma abacavir exposure after once- or twice-daily dosing regimens in infants and children up to age 12 years.16-20 These trials, in combination with PK modeling, demonstrated that once-daily abacavir dosing with either the tablet or liquid formulation provides comparable plasma PK exposures to twice-daily dosing of abacavir at the same total daily dose.21
Dosing and Formulations
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 600 mg of abacavir 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 the tablet formulation.4 There is no difference in the abacavir plasma Cmax and AUC for abacavir liquid formulation compared to tablet formulation.22 Doses of liquid abacavir formulation are similar to those used for weight band dosing with tablet formulations and might be considered in some situations, especially in rapidly growing younger children.
In all three abacavir dosing pediatric trials described above,16-19 only children who had low viral loads and who were clinically stable on twice-daily formulation of abacavir were eligible to change to once-daily abacavir dosing. Efficacy data from a 48-week follow-up in the ARROW trial demonstrated clinical non-inferiority of once-daily abacavir (336 children) versus twice-daily abacavir (333 children) in tablet formulation combined with a once- or twice-daily lamivudine-based antiretroviral regimen.8 To date, no clinical trials have been conducted involving children who initiated therapy with once-daily dosing of abacavir liquid formulation. 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. However, in infants and young children initiating therapy with liquid formulations of abacavir, twice-daily dosing is recommended, and switching to once-daily dosing after 6 months (24 weeks) should be considered if viral load is undetectable and CD4 cell count/percentage is stable (without decline).
Abacavir has less of an effect on mitochondrial function than the NRTIs zidovudine, stavudine, or didanosine,6,7 and less bone and renal toxicity when compared to TDF.13,23
- 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 sulfate [package insert]. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020977s030,020978s034lbl.pdf.
- Adkinson K, Mccoig C, Wolstenholme A, et al. Effect of sorbitol on lamivudine pharmacokinetics following administration of EPIVIR® solution in adults. Presented at: Conference on Retroviruses and Opportunistic Infections. 2017. Seattle, WA.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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: 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.