Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States

  •   Table of Contents

Download Guidelines

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors

Abacavir (Ziagen, ABC)

Last Updated: November 14, 2017; Last Reviewed: November 14, 2017

The available human and animal data suggest that abacavir does not increase the risk of major birth defects overall compared with the background rate.1

Animal Studies

Carcinogenicity
Abacavir is mutagenic and clastogenic in some in vitro and in vivo assays. In long-term carcinogenicity studies in mice and rats, malignant tumors of the preputial gland of males and the clitoral gland of females were observed in both species, and malignant hepatic tumors and nonmalignant hepatic and thyroid tumors were observed in female rats. The tumors were seen in rodents at doses that were 6 to 32 times that of human therapeutic exposure.1

Reproduction/Fertility
No effect of abacavir on reproduction or fertility in male and female rodents has been seen at doses of up to 500 mg/kg/day (about 8 times that of human therapeutic exposure based on body surface area).

Teratogenicity/Adverse Pregnancy Outcomes
Abacavir is associated with developmental toxicity (decreased fetal body weight and reduced crown-rump length) and increased incidence of fetal anasarca and skeletal malformations in rats treated with abacavir during organogenesis at doses of 1000 mg/kg (about 35 times that of human therapeutic exposure based on area under the curve [AUC]). Toxicity to the developing embryo and fetus (i.e., increased resorptions and decreased fetal body weight) occurred with administration of 500 mg/kg/day of abacavir to pregnant rodents. The offspring of female rats were treated with 500 mg/kg of abacavir, beginning at embryo implantation and ending at weaning. In these animals, an increased incidence of stillbirth and lower body weight was seen throughout life. However, in the rabbit, no evidence of drug-related developmental toxicity was observed and no increase in fetal malformations was observed at doses up to 700 mg/kg (about 8.5 times that of human therapeutic exposure).1

Placental and Breast Milk Passage
Abacavir crosses the placenta and is excreted into the breast milk of lactating rats.1

Human Studies in Pregnancy

Pharmacokinetics
In pregnant women, pharmacokinetic (PK) studies of 300 mg twice daily and2 600 mg daily concluded3 that the PK during pregnancy is equivalent to postpartum. A population PK study (266 samples from 150 pregnant women) found no effect of any co-variate (including age, body weight, pregnancy or gestational age) on abacavir PK.4 Thus, no dose adjustment for abacavir is needed during pregnancy.

Placental and Breast Milk Passage
Placental transfer of abacavir is high, with cord blood-to-maternal-plasma-concentration ratios at delivery of approximately 1.0.2,5 In the Mma Bana study,6 at 1 month postpartum, the median breast milk-to-plasma ratio for abacavir was 0.85 in the 15 women tested, and the drug was detected in the plasma of 1 of 9 breastfeeding infants whose mothers were receiving abacavir.

Teratogenicity/Adverse Pregnancy Outcomes
In the Antiretroviral Pregnancy Registry (APR), sufficient numbers of first-trimester exposures to abacavir in humans have been monitored to be able to detect at least a 1.5-fold increase in risk of overall birth defects. No such increase in birth defects has been observed with abacavir. Among cases of first-trimester abacavir exposure reported to the APR, the prevalence of birth defects was 2.98% (30 of 1007 births; 95% CI, 2.01% to 4.23%) compared with 2.72% in the U.S. population, based on Centers for Disease Control and Prevention surveillance.7 There was no association of birth defects with first-trimester exposure to abacavir in the SMARTT study (aOR 0.94 [0.53–1.65]),8 in the French Perinatal Study (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

Safety
Serious hypersensitivity reactions have been associated with abacavir therapy in non-pregnant adults, but these reactions have rarely been fatal; symptoms include fever, skin rash, fatigue, and gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain. Abacavir should not be restarted following a hypersensitivity reaction 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 highest risk and should not receive abacavir; HLA screening should be done before initiation of abacavir. Two meta-analyses have confirmed the association of this genotype and the hypersensitivity reaction.11,12

In the PHACS/SMARTT cohort (median follow-up: 2.4 years), after adjusting for birth cohort and other factors, use of abacavir by the mother during pregnancy led to no increase in the likelihood of adverse events for the infant in the following domains: metabolic, growth and development, cardiac, neurological, neurodevelopmental.13

Excerpt from Table 9a
Generic Name
(Abbreviation)
Trade Name
Formulation Dosing Recommendations Use in Pregnancy
Abacavir
(ABC)
Ziagen

(ABC/3TC)
Epzicom

(ABC/3TC/ZDV)
Trizivir

(ABC/3TC/DTG)
Triumeq
ABC (Ziagen):e
Tablet:
  • 300 mg
Solution:
  • 20 mg/mL
Epzicom:e
  • ABC 600 mg plus 3TC 300 mg tablet
Trizivir:e
  • ABC 300 mg plus 3TC 150 mg plus ZDV 300 mg tablet
Triumeq:
  • ABC 600 mg plus 3TC 300 mg plus DTG 50 mg tablet
Standard Adult Doses
ABC (Ziagen):
  • 300 mg twice daily or 600 mg once daily, without regard to food
Epzicom:
  • 1 tablet once daily without regard to food
Trizivir:
  • 1 tablet twice daily without regard to food
Triumeq:
  • 1 tablet daily without regard to food
PK in Pregnancy:
  • PK not significantly altered in pregnancy.
Dosing in Pregnancy:
  • No change in dose indicated.
High placental transfer to fetus.b

No evidence of human teratogenicity (can rule out 1.5-fold increase in overall birth defects).

Hypersensitivity reactions occur in approximately 5% to 8% of non-pregnant individuals; a much smaller percentage are fatal and are usually associated with re-challenge. Rate in pregnancy is unknown. Testing for HLA-B*5701 identifies patients at risk of reactions and should be done and documented as negative before starting ABC. Patients should be educated regarding symptoms of hypersensitivity reaction.
a Individual antiretroviral drug dosages may need to be adjusted in renal or hepatic insufficiency (for details, see the Adult and Adolescent Guidelines Appendix B, Table 7).
b Placental transfer categories—Mean or median cord blood/maternal delivery plasma drug ratio:
          High: >0.6
          Moderate: 0.3–0.6
          Low: <0.3
c See Teratogenicity section for discussion of EFV and risks in pregnancy.
d Only indicated for use in chronic hepatitis B virus infection in adults
e Generic formulation available
f WHO recommends maximum dose of 30 mg twice daily regardless of weight.

Key to Acronyms: 3TC = lamivudine; ABC = abacavir; DTG = dolutegravir; PK = pharmacokinetic; ZDV = zidovudine

References

  1. Abacavir [package insert]. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020977s030,020978s034lbl.pdf.
  2. Best BM, Mirochnick M, Capparelli EV, et al. Impact of pregnancy on abacavir pharmacokinetics. AIDS. 2006;20(4):553-560. Available at http://www.ncbi.nlm.nih.gov/pubmed/16470119.
  3. 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://www.ncbi.nlm.nih.gov/pubmed/26836789.
  4. 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 http://www.ncbi.nlm.nih.gov/pubmed/25070097.
  5. 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 http://www.ncbi.nlm.nih.gov/pubmed/15504861.
  6. 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 http://www.ncbi.nlm.nih.gov/pubmed/23183881.
  7. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 Jan 1989–1 January 2016. Wilmington, NC: Registry Coordinating Center. 2016. Available at
  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 http://www.ncbi.nlm.nih.gov/pubmed/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. Available at http://www.ncbi.nlm.nih.gov/pubmed/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 Infectious Diseases. 2014;14:700. Available at http://www.ncbi.nlm.nih.gov/pubmed/25808698.
  11. 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 http://www.ncbi.nlm.nih.gov/pubmed/25934581.
  12. 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 http://www.ncbi.nlm.nih.gov/pubmed/25877443.
  13. 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://www.ncbi.nlm.nih.gov/pubmed/26731758.

Download Guidelines