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Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors

Abacavir (Ziagen, ABC)

(Last updated: April 29, 2016; last reviewed: April 29, 2016)

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/Developmental Toxicity
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.1,2

Human Studies in Pregnancy

Pharmacokinetics
A Phase I study of abacavir in pregnant women indicates that the AUC drug concentration during pregnancy was similar to that at 6 to 12 weeks postpartum and in non-pregnant individuals.3 A population pharmacokinetics (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 1.0.3,5 In the Mma Bana study,2 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
In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to abacavir in humans have been monitored to be able to detect at least a 2-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 Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.9% (29 of 993 births; 95% CI, 2.0% to 4.2%) compared with 2.7% in the U.S. population, based on Centers for Disease Control and Prevention surveillance.6 There was no association of birth defects with first-trimester exposure to abacavir in the SMARTT study (aOR 0.94 [0.53–1.65]),7 in the French Perinatal Study (aOR 1.01, [0.73–1.41]),8 or in a series of 897 births to HIV-infected women in Spain between 2000 to 2009 (aOR 0.99, [0.34–2.87]).9

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; HLA screening should be done before initiation of abacavir. Two meta-analyses have confirmed the association of this genotype and the hypersensitivity reaction.10,11

Excerpt from Table 8a
Generic Name
(Abbreviation)
Trade Name
Formulation  Dosing Recommendations Use in Pregnancy

Abacavir
(ABC)
Ziagen

(ABC/3TC)
Epzicom
 
(ABC/3TC/ZDV)
Trizivir
            (ABC/DTG/3TC)
Triumeq

ABC (Ziagen)
Tablet:
  • 300 mg
Solution:
  • 20 mg/mL
Epzicom:
  • ABC 600 mg plus 3TC 300 mg tablet
Trizivir:
  • ABC 300 mg plus 3TC 150 mg plus ZDV 300 mg tablet 
Triumeq:
  • ABC 600 mg plus DTG 50 mg plus 3TC 300 mg
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 2-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 Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 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

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

References

  1. Abacavir (Ziagen) [package insert]. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020977s030,020978s034lbl.pdf. Accessed February 15, 2016.
  2. 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.
  3. 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.
  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. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 Jan 1989–31 July 2015. Wilmington, NC: Registry Coordinating Center. 2015. Available at http://www.apregistry.com/. Accessed February 15, 2016.
  7. 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.
  8. 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.
  9. 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 http://www.ncbi.nlm.nih.gov/pubmed/25808698.
  10. 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.
  11. 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.

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