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: April 16, 2019; Last Reviewed: April 16, 2019
|Abacavir (ABC, Ziagen)
For additional information see Drugs@FDA: https://www.accessdata.fda.gov/scripts/cder/daf/
Tablets: 300 mg (scored)
Fixed-Dose Combination Tablets:
|Dosing Recommendations||Selected Adverse Events|
|Neonate and Infant Dose
Child and Adolescent (Weighing ≥25 kg) and Adult Dose:
Child and Adolescent (Weighing ≥25 kg) and Adult Dose:
Child and Adolescent (Weighing ≥25 kg) and Adult Dose:
Child and Adolescent (Weighing ≥30 kg) and Adult Dose:
- Abacavir does not inhibit, nor is it metabolized by, hepatic cytochrome P450 enzymes. Therefore, it does not cause significant changes in the clearance of agents that are metabolized through these pathways, such as protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors. Abacavir plasma concentrations can decrease when abacavir is used concurrently with the boosted PIs atazanavir/ritonavir, lopinavir/ritonavir, and darunavir/ritonavir.1-3 The mechanism and the clinical significance of the drug interactions with these PIs are unknown. There are currently no recommendations for dose adjustments when coadministering abacavir and one of these boosted PIs.
- Alcohol exposure (0.7 g per kg ethanol, which is equivalent to five alcoholic drinks) has been shown to interfere with abacavir metabolism by affecting activity of alcohol dehydrogenase and glucuronyl transferase. This interference led to a 41% increase in abacavir area under the curve plasma exposure in adult men with HIV who received abacavir 600 mg daily.4
- Abacavir oral solution contains sorbitol, which decreased the exposure of lamivudine solution in adults when the drugs were administered concurrently.5
- More common: Nausea, vomiting, fever, headache, diarrhea, rash, anorexia.
- Less common (more severe): Serious and sometimes fatal hypersensitivity reactions (HSRs) that have been observed in approximately 5% of adults and children (the rate varies by race/ethnicity) receiving abacavir. HSR to abacavir is a multi-organ clinical syndrome that is usually characterized by rash or signs or symptoms in two or more of the following groups:
- Constitutional, including malaise, fatigue, or achiness
- Gastrointestinal signs and symptoms, including nausea, vomiting, diarrhea, or abdominal pain
- Respiratory signs and symptoms, 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. HSRs generally occur during the first 6 weeks of therapy, but they have also been reported after a single dose of abacavir. If an HSR is suspected, abacavir should be stopped immediately and not restarted—hypotension and death may occur upon re-challenge. The risk of an abacavir HSR is associated with the presence of HLA-B*5701 allele; the risk is greatly reduced by not using abacavir in those who test positive for the HLA-B*5701 allele.
- Rare: Increased levels of liver enzymes, elevated blood glucose levels, elevated triglycerides (see cardiac risk below). Pancreatitis, lactic acidosis, and severe hepatomegaly with steatosis, including fatal cases, have been reported.
- Rare: Drug reaction (or rash) with eosinophilia and systemic symptoms (DRESS) syndrome.
- Rare: Several observational cohort studies suggest an increased risk of myocardial infarction in adults who are currently using abacavir or who have recently used abacavir; however, other studies have not substantiated this finding, and there are no data on cardiovascular risks associated with abacavir use in children.
Abacavir is approved by the Food and Drug Administration (FDA) for use in children with HIV aged ≥3 months as part of the nucleoside reverse transcriptase inhibitor (NRTI) component of antiretroviral therapy (ART). The World Health Organization (WHO), however, recommends using abacavir as a component of the NRTI backbone for children weighing ≥3 kg, starting at 4 weeks of age (see WHO Dosages of Antiretroviral Drugs). This recommendation is based on the general principle of using non-thymidine analogues in first-line regimens and thymidine analogues in second-line regimens. This recommendation also takes into account the availability of President’s Emergency Plan for AIDS Relief-approved pediatric generic abacavir formulations, including coformulations that include lamivudine, and the cost of ART in resource-limited settings. No systematic safety assessment has been conducted for using abacavir in children weighing <14 kg.
Both the once-daily and twice-daily doses of abacavir have demonstrated durable antiviral efficacy in pediatric clinical trials, and this drug is of comparable efficacy to other NRTIs in children.6-10
Pharmacokinetics in Children
Pharmacokinetic (PK) studies of abacavir in children aged <12 years have demonstrated that metabolic clearance of abacavir in adolescents and young adults (aged 13 years–25 years) is slower than that observed in younger children and approximates clearance seen in older adults.11
The PKs of abacavir administered once daily in children with HIV aged 3 months through 12 years were evaluated in three crossover, open-label PK trials of twice-daily versus once-daily dosing of abacavir and lamivudine (PENTA 13 [N = 14], PENTA 15 [N = 18], and ARROW [N = 36]).4,12-15 The data from these three pediatric trials was used to develop a model for abacavir PKs; this model predicted that systemic plasma abacavir exposure after once-daily dosing would be equivalent to the exposure seen after twice-daily dosing in infants and children aged ≤12 years.12-16 These trials, in combination with PK modeling, demonstrated that once-daily abacavir dosing with either the tablet or the liquid formulation provides plasma PK exposures that are comparable to those seen with twice-daily dosing of abacavir at the same total daily dose.17
Dosing and Formulations
Initially, the recommended dose for pediatric use was abacavir 8 mg/kg twice daily, for a total of 16 mg/kg per day. A 2015 FDA review suggested that a total daily dose of abacavir 600 mg could be safely used in a person weighing 25 kg (i.e., abacavir 24 mg/kg per day, a 50% increase from the previously recommended dose). The weight-band dosing table recommends total daily doses as high as abacavir 21.5 mg/kg per day to abacavir 22.5 mg/kg per day when treating patients with the tablet formulation.4 There is no difference in the abacavir plasma Cmax and AUC for the abacavir liquid formulation compared to the tablet formulation.18 Doses of liquid abacavir formulation are similar to those used for weight-band dosing with tablet formulations and should be considered for use in younger children who are unable to swallow a pill.
In all three abacavir dosing pediatric trials described above,12-15 only children who had low viral loads and who were clinically stable on the twice-daily dose 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 noninferiority of once-daily abacavir (N = 336) versus twice-daily abacavir (N = 333) in tablet form combined with a once-daily 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, initiating therapy with once-daily dosing of abacavir at a dose of 16 mg/kg (with a maximum dose of abacavir 600 mg) is recommended. However, in infants and young children who initiate therapy with the liquid formulation of abacavir, twice-daily dosing is recommended. Switching to once-daily dosing with the liquid or pill formulation could be considered in clinically stable children with suppressed viral loads and stable CD4 T lymphocyte cell counts.
Abacavir has less of an effect on mitochondrial function than the NRTIs zidovudine, stavudine, or didanosine,6,7 and less bone and renal toxicity than TDF.19,20
- 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 [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 (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: https://www.ncbi.nlm.nih.gov/pubmed/11888583.
- 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.
- 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.
- 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.
- 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.
- 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.