Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors

Abacavir (Ziagen, ABC)

Summary

• No dose adjustments are required for abacavir (ABC) during pregnancy.
• First-trimester exposure to ABC is not associated with increased risk of congenital abnormalities.
• HLA-B*5701 screening should be done before initiating ABC. Patients who test positive for HLA-B*5701 are at the highest risk of hypersensitivity reactions and should not receive ABC.

Human Studies in Pregnancy

Pharmacokinetics

In pregnant women, pharmacokinetic (PK) studies of ABC 300 mg twice daily¹ and ABC 600 mg once daily² showed that the PK during pregnancy are equivalent to the PK observed during the postpartum period. A population PK study (analyzing 266 plasma samples from 150 pregnant women) found no effect of any covariate (including age, body weight, pregnancy, or gestational age) on ABC PK.³ Thus, no dose adjustment for ABC is needed during pregnancy.

Placental and Breast Milk Passage

Placental transfer of ABC is high, with ratios of ABC concentration in cord blood–to–ABC concentration in maternal plasma at delivery of approximately 1.0.^1,4 In the Mma Bana study,⁵ the median breast milk–to–plasma ratio for ABC was 0.85 in the 15 women tested at 1 month postpartum, and the drug was detected in the plasma of one out of nine breastfeeding infants whose mothers were receiving ABC. In the Swiss Mother and Child HIV Cohort nested study, ABC was measurable in four breastfeeding infants; the relative infant dose was 0.34%.⁶

Teratogenicity/Adverse Pregnancy Outcomes

The Antiretroviral Pregnancy Registry has monitored sufficient numbers of first-trimester exposures to ABC to detect at least a 1.5-fold increase in the risk of overall birth defects and at least a twofold increase in the risk of cardiovascular and genitourinary defects (which are the more common classes of birth defects in the general population). No such increase in the risk of birth defects has been observed with ABC. Among the cases of first-trimester ABC exposure that have been reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 3.2% (47 infants out of 1,455 live births; 95% confidence interval, 2.4% to 4.3%) compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention surveillance.⁷ First-trimester exposure to ABC was not associated with birth defects in the Surveillance Monitoring for Antiretroviral Therapy Toxicities (SMARTT) study (adjusted odds ratio [aOR] 0.94, 0.53–‍1.65),⁸ in the French Perinatal Cohort (aOR 1.01, 0.73–1.41),⁹ or in a series of 897 births to women with HIV in Spain between 2000 and 2009 (aOR 0.99, 0.34–2.87).¹⁰

Pregnancy outcomes were similar between pregnant women who received an ABC/lamivudine (3TC) backbone (n = 252) and women who received a tenofovir disoproxil fumarate/emtricitabine backbone (n = 661) in the Italian National Program on Surveillance on Antiretroviral Treatment in Pregnancy. However, total cholesterol levels were higher in the group that received ABC.¹¹

Ten percent of participants (711 pregnancies) received ABC plus 3TC in the European Pregnancy Paediatric HIV Cohort Collaboration (EPPICC) study group. The proportions of preterm deliveries and small-for-gestational-age infants that occurred among women who received ABC were similar to those seen among women who received other antiretroviral drugs.¹²

Other Safety Information

Serious hypersensitivity reactions (HSRs) have been associated with ABC therapy in nonpregnant adults, but these reactions rarely have been fatal; symptoms include fever, skin rash, fatigue, and gastrointestinal symptoms such as nausea, vomiting, diarrhea, and abdominal pain. ABC should not be restarted following an HSR because more severe symptoms will occur within hours and may include life-threatening hypotension and death. Patients who test positive for HLA-B*5701 are at the highest risk of HSRs and should not receive ABC; HLA-B*5701 screening should be done before initiating ABC. Two meta-analyses have confirmed the association between this genotype and the HSR.^13,14

After adjusting for birth cohort and other factors, the Pediatric HIV/AIDS Cohort Study (PHACS)/‌SMARTT study (which followed participants for a median of 2.4 years) reported no increases in the likelihood of metabolic, cardiac, neurological, growth and development, or neurodevelopmental adverse events among infants whose mothers took ABC during pregnancy.¹⁵

Animal Studies

Carcinogenicity

Preputial and clitoral gland tumors, and malignant hepatic tumors, were seen in rodents at exposures that were 6 to 32 times those observed in humans who received the recommended dose.¹⁶

Reproduction/Fertility

No effect on reproduction or fertility in rodents was seen at doses that were about eight times the exposures seen in humans who received the recommended dose. ¹⁶

Teratogenicity/Adverse Pregnancy Outcomes

Decreased fetal body weight and reduced crown–rump length were seen in rats treated during organogenesis. An increased number of resorptions and an increased incidence of stillbirths occurred among rats treated from embryo implantation through weaning of the pups. No developmental toxicities and no increases in fetal malformations occurred in pregnant rabbits at up to the highest dose evaluated, resulting in exposures approximately nine times the human exposure at the recommended dose.¹⁶

Placental and Breast Milk Passage

ABC crosses the placenta and is excreted into the breast milk of lactating rats.¹⁶

Excerpt from Table 14

Note: When using fixed-dose combination (FDC) tablets, refer to other sections in Appendix B and Table 14 in the Perinatal Guidelines for information about the dosing and safety of individual drug components of the FDC tablet during pregnancy.

References

1. Best BM, Mirochnick M, Capparelli EV, et al. Impact of pregnancy on abacavir pharmacokinetics. AIDS. 2006;20(4):553-560. Available at: https://pubmed.ncbi.nlm.nih.gov/16470119.
2. Schalkwijk S, Colbers A, Konopnicki D, et al. The pharmacokinetics of abacavir 600 mg once daily in HIV-1-positive pregnant women. AIDS. 2016;30(8):1239-1244. Available at: https://pubmed.ncbi.nlm.nih.gov/26836789.
3. Fauchet F, Treluyer JM, Preta LH, et al. Population pharmacokinetics of abacavir in pregnant women. Antimicrob Agents Chemother. 2014;58(10):6287-6289. Available at: https://pubmed.ncbi.nlm.nih.gov/25070097.
4. Chappuy H, Treluyer JM, Jullien V, et al. Maternal-fetal transfer and amniotic fluid accumulation of nucleoside analogue reverse transcriptase inhibitors in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother. 2004;48(11):4332-4336. Available at: https://pubmed.ncbi.nlm.nih.gov/15504861.
5. Shapiro RL, Rossi S, Ogwu A, et al. Therapeutic levels of lopinavir in late pregnancy and abacavir passage into breast milk in the Mma Bana Study, Botswana. Antivir Ther. 2013;18(4):585-590. Available at: https://pubmed.ncbi.nlm.nih.gov/23183881.
6. Aebi-Popp K, Kahlert CR, Crisinel PA, et al. Transfer of antiretroviral drugs into breastmilk: a prospective study from the Swiss Mother and Child HIV Cohort Study. J Antimicrob Chemother. 2022;77(12):3436-3442. Available at: https://pubmed.ncbi.nlm.nih.gov/36177836.
7. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 January 1989–31 January Morrisville, NC: Registry Coordinating Center; 2023.Available at: https://www.apregistry.com.
8. Williams PL, Crain MJ, Yildirim C, et al. Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants. JAMA Pediatr. 2015;169(1):48-55. Available at: https://pubmed.ncbi.nlm.nih.gov/25383770.
9. Sibiude J, Le Chenadec J, Bonnet D, et al. In utero exposure to zidovudine and heart anomalies in the ANRS French perinatal cohort and the nested PRIMEVA randomized trial. Clin Infect Dis. 2015;61(2):270-280. Available at: https://pubmed.ncbi.nlm.nih.gov/25838291.
10. Prieto LM, Gonzalez-Tome MI, Munoz E, et al. Birth defects in a cohort of infants born to HIV-infected women in Spain, 2000-2009. BMC Infect Dis. 2014;14:700. Available at: https://pubmed.ncbi.nlm.nih.gov/25808698.
11. Floridia M, Pinnetti C, Ravizza M, et al. Brief report: abacavir/lamivudine and tenofovir/emtricitabine in pregnant women with HIV: laboratory and clinical outcomes in an observational national study. J Acquir Immune Defic Syndr. 2018;78(1):99-104. Available at: https://pubmed.ncbi.nlm.nih.gov/29406430.
12. European Pregnancy Paediatric HIV Cohort Collaboration Study Group. Nucleoside reverse transcriptase inhibitor backbones and pregnancy outcomes. AIDS. 2019;33(2):295-304. Available at: https://pubmed.ncbi.nlm.nih.gov/30562172.
13. Sousa-Pinto B, Pinto-Ramos J, Correia C, et al. Pharmacogenetics of abacavir hypersensitivity: a systematic review and meta-analysis of the association with HLA-B*57:01. J Allergy Clin Immunol. 2015;136(4):1092-1094 e1093. Available at: https://pubmed.ncbi.nlm.nih.gov/25934581.
14. Tangamornsuksan W, Lohitnavy O, Kongkaew C, et al. Association of HLA-B*5701 genotypes and abacavir-induced hypersensitivity reaction: a systematic review and meta-analysis. J Pharm Pharm Sci. 2015;18(1):68-76. Available at: https://pubmed.ncbi.nlm.nih.gov/25877443.
15. Williams PL, Hazra R, Van Dyke RB, et al. Antiretroviral exposure during pregnancy and adverse outcomes in HIV-exposed uninfected infants and children using a trigger-based design. AIDS. 2016;30(1):133-144. Available at: https://pubmed.ncbi.nlm.nih.gov/26731758.
16. Ziagen (abacavir) package insert [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020977s035,020978s038lbl.pdf.