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 14, 2020; Last Reviewed: April 14, 2020
|Abacavir (ABC, Ziagen)|
Pediatric Oral Solution: 20 mg/mL
Tablet: 300 mg (scored)
For additional information, see Drugs@FDA or DailyMed.
|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 (ABC) 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.
- ABC plasma concentrations can decrease when ABC 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 ABC 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 ABC metabolism by affecting the activity of alcohol dehydrogenase and glucuronyl transferase. This interference led to a 41% increase in ABC area under the curve plasma exposure in adult men with HIV who received ABC 600 mg daily.4
- ABC oral solution contains sorbitol, which decreased the exposure of lamivudine (3TC) oral 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) who were receiving ABC. The HSR to ABC 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 symptoms, 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 ABC. If an HSR is suspected, ABC should be stopped immediately and not restarted—hypotension and death may occur upon rechallenge. The risk of an ABC HSR is associated with the presence of the HLA-B*5701 allele; the risk is greatly reduced by not using ABC 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 that there is an increased risk of myocardial infarction in adults who are currently using ABC or who have recently used ABC; however, other studies have not substantiated this finding, and there are no prospective data on the cardiovascular risks that are associated with ABC use in children. One cohort study of South African adolescents (in which 385 participants had HIV and 63 participants were HIV-negative controls) with a median age of 12 years reported an association between ABC exposure and insulin resistance, which was evaluated using homeostatic model assessment. These findings suggest that the use of ABC may be a cardiovascular risk factor for young people with perinatally acquired HIV.6
ABC 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 ABC as a component of the NRTI backbone for children weighing ≥3 kg, starting at 4 weeks of age (see Dosages of Antiretroviral Drugs from WHO). 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 ABC formulations, including coformulations that include 3TC, and the cost of antiretroviral (ARV) drugs in resource-limited settings. No systematic safety assessment has been conducted for using ABC in children weighing <14 kg.
Both the once-daily and twice-daily doses of ABC have demonstrated durable antiviral efficacy in pediatric clinical trials that is comparable to the efficacy observed for other NRTIs in children.7-11
Pharmacokinetics in Children
Pharmacokinetic (PK) studies of ABC in children aged <12 years have demonstrated that metabolic clearance of ABC in adolescents and young adults (aged 13–25 years) is slower than that observed in younger children and approximates clearance seen in older adults.12
The PKs of ABC 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 ABC and 3TC (PENTA 13 [n = 14], PENTA 15 [n = 18], and ARROW [n = 36]).4,13-16 The data from these three pediatric trials were used to develop a model for ABC PKs; this model predicted that systemic plasma ABC exposure after once-daily dosing would be equivalent to the exposure seen after twice-daily dosing in infants and children aged ≤12 years.13-17 Both these trials and PK modeling have demonstrated that once-daily dosing with either the tablet or the liquid formulation of ABC produces plasma exposures that are comparable to those seen with a twice-daily dosing schedule that uses the same total daily dose of ABC.18
Dosing and Formulations
Initially, the recommended dose for pediatric use was ABC 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 ABC 600 mg could be safely used in a person weighing 25 kg (i.e., ABC 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 ABC 21.5 mg/kg per day to ABC 22.5 mg/kg per day when treating patients with the tablet formulation.4 There is no difference in the ABC plasma Cmax and area under the curve for the ABC liquid formulation compared to the tablet formulation.19 Doses of the liquid ABC 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 ABC dosing pediatric trials described above,13-16 only children who had low viral loads and who were clinically stable on the twice-daily dose of ABC were eligible to change to once-daily ABC dosing. Efficacy data from a 48-week follow-up in the ARROW trial demonstrated clinical noninferiority of once-daily ABC (n = 336) versus twice-daily ABC (n = 333) in tablet form combined with a once-daily or twice-daily 3TC-based ARV regimen.9 To date, no clinical trials have been conducted involving children who initiated therapy with once-daily dosing of the ABC liquid formulation. In children who can be treated with pill formulations, initiating therapy with once-daily dosing of ABC at a dose of 16 mg/kg (with a maximum dose of ABC 600 mg) is recommended. However, twice-daily dosing is recommended for infants and young children who initiate therapy with the liquid formulation of ABC. 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.
ABC has less of an effect on mitochondrial function than the NRTIs zidovudine, stavudine, or didanosine,7,8 and less bone and renal toxicity than tenofovir disoproxil fumarate.20,21
- 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. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020977s033s034,020978s036s037lbl.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, Washington.
- Frigati LJ, Jao J, Mahtab S, et al. Insulin resistance in South African youth living with perinatally acquired HIV receiving antiretroviral therapy. AIDS Res Hum Retroviruses. 2019;35(1):56-62. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30156434.
- 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, Georgia.
- 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. 2013;75(6):1525-35. 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.