Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States
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
Zidovudine (Retrovir, AZT, ZDV)
Last Updated: November 14, 2017; Last Reviewed: November 14, 2017
Available evidence does not suggest that zidovudine use by pregnant women is associated with an increased risk of adverse fetal or pregnancy outcomes.1
Zidovudine was shown to be mutagenic in two in vitro assays and clastogenic in one in vitro and two in vivo assays, but not cytogenic in a single-dose in vivo rat study. Long-term carcinogenicity studies have been performed with zidovudine in mice and rats.2 In mice, 7 late-appearing (>19 months) vaginal neoplasms (5 non-metastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of an animal given an intermediate dose. No vaginal tumors were found at the lowest dose. In rats, 2 late-appearing (>20 months), non-metastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex in either species. At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by area under the curve [AUC]) was approximately three times (mice) and 24 times (rats) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours. How predictive the results of rodent carcinogenicity studies may be for humans is unknown.1
Two trans-placental carcinogenicity studies were conducted in mice.3,4 In 1 study, zidovudine was administered at doses of 20 mg/kg/day or 40 mg/kg/day from gestational day 10 through parturition and lactation, with postnatal dosing continuing in offspring for 24 months.4 The drug doses administered in this study produced zidovudine exposures approximately three times the estimated human exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. In a second study, zidovudine was administered at maximum tolerated doses of 12.5 mg/day or 25 mg/day (~1,000 mg/kg non-pregnant body weight or ~450 mg/kg of term body weight) to pregnant mice from days 12 to 18 of gestation.3 There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose of zidovudine.
When administered to male and female rats at doses up to seven times the usual adult dose based on body surface area, zidovudine had no effect on fertility, as judged by rates of conception. Zidovudine has been shown to have no effect on reproduction or fertility in rodents. A dose-related cytotoxic effect on preimplantation mouse embryos can occur, with inhibition of blastocyst and post-blastocyst development at zidovudine concentrations similar to levels achieved with human therapeutic doses.5
Teratogenicity/Adverse Pregnancy Outcomes
In animal reproduction studies, administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (expressed as “area under the curve”, AUC) approximately 33 times higher than human exposures at the recommended clinical dose. However, no embryotoxicity was observed after administration to pregnant rats during organogenesis at doses that produced AUC approximately 117 times higher than clinical exposures. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced exposures approximately 108 times higher than the clinical exposure. No embryotoxicity was observed at doses that produced exposures approximately 23 times higher than the clinical exposure.1
In an additional teratology study in rats, a dose of 3000 mg/kg/day (very near the oral median lethal dose in rats of 3683 mg/kg) caused marked maternal toxicity and an increase in incidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations (estimated AUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg/day). No evidence of teratogenicity was seen in this experiment at doses of 600 mg/kg/day or less.
Human Studies in Pregnancy
Zidovudine pharmacokinetics (PK) are not significantly altered by pregnancy, and standard adult doses are recommended.6,7 A population PK analysis following oral and intravenous (IV) zidovudine doses during pregnancy and labor found high fetal exposure to zidovudine with current IV intrapartum dosing regimens. Simulations from this modeling suggested that reduced intrapartum zidovudine dosing regimens might provide lower but still adequate fetal zidovudine exposures.8 However, standard dosing of IV zidovudine during labor continues to be recommended. In pregnant women, as with nonpregnant adults, intracellular zidovudine triphosphate concentrations do not vary with plasma concentrations, over a wide range of plasma zidovudine concentrations.9
Placental and Breast Milk Passage
Zidovudine rapidly crosses the human placenta, achieving cord-to-maternal-blood ratios of about 0.80. The ratio of zidovudine in amniotic fluid to that in maternal plasma is 1.5.10 Zidovudine is excreted into human breast milk with breast milk-to-maternal-plasma zidovudine concentration ratios ranging from 0.44 to 1.35. No zidovudine was detectable in the plasma of nursing infants who received zidovudine only via breast milk.11-13
Teratogenicity/Adverse Pregnancy Outcomes
In PACTG 076, the incidence of minor and major congenital abnormalities was similar between zidovudine and placebo groups, and no specific patterns of defects were seen.6,14 Similarly, no increase in birth defects was detected among infants enrolled in the large observational cohorts PACTG 219/219C and P1025.15,16 A previous report from the Women and Infants Transmission Study described a 10-fold increased risk of hypospadias, but this finding was not confirmed in a more detailed analysis.17,18 In the PHACS/SMARTT cohort, there was no association between first-trimester exposure and congenital anomalies.19 In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to zidovudine have been monitored to be able to detect at least a 1.5-fold increased risk of overall birth defects and a 2-fold increased incidence of defects in the more common classes, including the cardiovascular and genitourinary systems. No such increase in birth defects has been observed with zidovudine. With first-trimester zidovudine exposure, the prevalence of birth defects was 3.2% (133 of 4161 births; 95% CI, 2.7% to 3.8%), compared with a total prevalence in the US population of 2.72%, based on Centers for Disease Control and Prevention surveillance.20 Similarly, a series of 897 infants exposed to HIV born in Spain during 2000 through 2009 reported no increase in birth defects among infants with first-trimester zidovudine exposure (aOR 1.21 [0.56–2.63]).21
The French Perinatal Cohort reported that first-trimester zidovudine exposure was associated with congenital heart defects (1.5% of 3,262 exposures vs. 0.7% of non-exposures; aOR=2.2 [95% CI, 1.5–3.2]). However, an analysis of cardiac defects among all prenatal zidovudine-exposed infants in the Antiretroviral Pregnancy Registry (n = 13,703) reported no difference in the prevalence of ventricular septal defect and congenital heart defects among infants exposed to zidovudine-containing regimens (9/4,000 first trimester, rate 0.23; 22/9,047 later, rate 0.24, P = 1.00) and zidovudine-non-containing regimens (2/1,839 first trimester, rate 0.11; 3/538 later, rate 0.56, P = 0.08).22
In the PRIMEVA trial, mothers were randomized to antepartum treatment with zidovudine/lamivudine/lopinavir/ritonavir or lopinavir/ritonavir. Female infants of women in the first group had a higher left ventricular shortening fraction at 1 month and increased posterior wall thickness at 1 year, suggestive of myocardial remodeling, when compared to infants whose mothers received lopinavir/ritonavir alone.23 In a study that performed fetal echocardiography of 42 HIV fetuses exposed to HIV who were not infected and 84 fetuses without HIV exposure, multivariate analysis revealed that maternal zidovudine treatment was associated with thicker myocardial walls and smaller left ventricular cavities among infants exposed to zidovudine compared to other infants with or without HIV exposure, and maternal zidovudine treatment was the only factor significantly associated with fetal cardiac changes.24
Cancer has been observed no more frequently among zidovudine-exposed infants than among other HIV-exposed or HIV-unexposed infants in a long-term follow-up study for the original PACTG 076 study,25 in prospective cohort studies,26 and in matches between HIV surveillance and cancer registries.27,28
Other Safety Information
In the placebo-controlled perinatal trial PACTG 076, no difference in disease progression was seen between women who received zidovudine and those who received a placebo, based on follow-up through 4 years postpartum.29
No differences in immunologic, neurologic, or growth parameters were seen between PACTG 076 infants with in utero zidovudine exposure and those who received a placebo, based on nearly 6 years of follow-up.14,25
Mitochondrial dysfunction in mothers and infants exposed to nucleoside reverse transcriptase inhibitors (NRTIs) during pregnancy has been described in some case reports, case series, prospective cohorts, and surveillance systems, but not in others. The result of the dysfunction, although fatal in a few cases, is more often asymptomatic and self-limited (e.g., leukopenia, anemia). At present, while a recognized possibility, the risk of NRTI-associated mitochondrial dysfunction in these mother-infant pairs does not outweigh the clear benefit of these drugs in preventing perinatal HIV transmission.
The PHACS/SMARTT cohort used a “trigger-based design” in which a number of domains (e.g., metabolic) had predetermined “triggers;” children meeting the definition of a trigger were further investigated to determine if they had met the definition of a “case” in that domain. The study found that after adjusting for birth cohort and other factors, zidovudine was associated with increased risk of meeting the study’s definition of a metabolic case (RR=1.69, 95% CI, 1.08–2.64).30,31
|Formulation||Dosing Recommendations||Use in Pregnancy|
Note: Generics are approved for all formulations
|Standard Adult Dos
PK in Pregnancy:
|High placental transfer to fetus.b
No evidence of human teratogenicity (can rule out 1.5-fold increase in overall birth defects).
a Individual ARV 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:
c See Teratogenicity section for discussion of EFV and risks in pregnancy.
d Only indicated for use in chronic HBV infection in adults
e Generic formulation available
f WHO recommends maximum dose of 30 mg regardless of weight.
Key to Acronyms: 3TC = lamivudine; ABC = abacavir; AZT = zidovudine; EFV = efavirenz; IV = intravenous; PK = pharmacokinetic; TID = three times a day; ZDV = zidovudine
- Zidovdine [package insert]. Food and Drug Administration. 2017. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019655s055,019910s042,019951s033lbl.pdf.
- Ayers KM, Clive D, Tucker WE, Jr., Hajian G, de Miranda P. Nonclinical toxicology studies with zidovudine: genetic toxicity tests and carcinogenicity bioassays in mice and rats. Fundam Appl Toxicol. 1996;32(2):148-158. Available at http://www.ncbi.nlm.nih.gov/pubmed/8921318.
- Olivero OA, Anderson LM, Diwan BA, et al. Transplacental effects of 3'-azido-2',3'-dideoxythymidine (AZT): tumorigenicity in mice and genotoxicity in mice and monkeys. Journal of the National Cancer Institute. 1997;89(21):1602-1608. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9362158&dopt=Abstract.
- Ayers KM, Torrey CE, Reynolds DJ. A transplacental carcinogenicity bioassay in CD-1 mice with zidovudine. Fundam Appl Toxicol. 1997;38(2):195-198. Available at http://www.ncbi.nlm.nih.gov/pubmed/9299194.
- Toltzis P, Marx CM, Kleinman N, Levine EM, Schmidt EV. Zidovudine-associated embryonic toxicity in mice. J Infect Dis. 1991;163(6):1212-1218. Available at http://www.ncbi.nlm.nih.gov/pubmed/2037787.
- Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994;331(18):1173-1180. Available at http://www.ncbi.nlm.nih.gov/pubmed/7935654.
- O'Sullivan MJ, Boyer PJ, Scott GB, et al. The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants: phase I acquired immunodeficiency syndrome clinical trials group study (protocol 082). Zidovudine Collaborative Working Group. Am J Obstet Gynecol. 1993;168(5):1510-1516. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8098905.
- Fauchet F, Treluyer JM, Valade E, et al. Maternal and fetal zidovudine pharmacokinetics during pregnancy and labour: too high dose infused at labour? Br J Clin Pharmacol. 2014;78(6):1387-1396. Available at http://www.ncbi.nlm.nih.gov/pubmed/25040510.
- Kinai E, Kato S, Hosokawa S, et al. High plasma concentrations of zidovudine (AZT) do not parallel intracellular concentrations of AZT-triphosphates in infants during prevention of mother-to-child HIV-1 transmission. J Acquir Immune Defic Syndr. 2016;72(3):246-253. Available at https://www.ncbi.nlm.nih.gov/pubmed/26859826.
- Bennetto-Hood C, Bryson YJ, Stek A, King JR, Mirochnick M, Acosta EP. Zidovudine, lamivudine, and nelfinavir concentrations in amniotic fluid and maternal serum. HIV Clin Trials. 2009;10(1):41-47. Available at http://www.ncbi.nlm.nih.gov/pubmed/19362995.
- Mirochnick M, Thomas T, Capparelli E, et al. Antiretroviral concentrations in breast-feeding infants of mothers receiving highly active antiretroviral therapy. Antimicrob Agents Chemother. 2009;53(3):1170-1176. Available at http://www.ncbi.nlm.nih.gov/pubmed/19114673.
- Palombi L, Pirillo MF, Andreotti M, et al. Antiretroviral prophylaxis for breastfeeding transmission in Malawi: drug concentrations, virological efficacy and safety. Antivir Ther. 2012;17(8):1511-1519. Available at http://www.ncbi.nlm.nih.gov/pubmed/22910456.
- Corbett AH, Kayira D, White NR, et al. Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to 24 weeks post partum: results of the BAN Study. Antivir Ther. 2014. Available at http://www.ncbi.nlm.nih.gov/pubmed/24464632.
- Sperling RS, Shapiro DE, McSherry GD, et al. Safety of the maternal-infant zidovudine regimen utilized in the Pediatric AIDS Clinical Trial Group 076 Study. AIDS. 1998;12(14):1805-1813. Available at http://www.ncbi.nlm.nih.gov/pubmed/9792381.
- Brogly SB, Abzug MJ, Watts DH, et al. Birth defects among children born to human immunodeficiency virus-infected women: pediatric AIDS clinical trials protocols 219 and 219C. Pediatr Infect Dis J. 2010;29(8):721-727. Available at http://www.ncbi.nlm.nih.gov/pubmed/20539252.
- Knapp KM, Brogly SB, Muenz DG, et al. Prevalence of congenital anomalies in infants with in utero exposure to antiretrovirals. Pediatr Infect Dis J. 2012;31(2):164-170. Available at http://www.ncbi.nlm.nih.gov/pubmed/21983213.
- Watts DH, Li D, Handelsman E, et al. Assessment of birth defects according to maternal therapy among infants in the Women and Infants Transmission Study. J Acquir Immune Defic Syndr. 2007;44(3):299-305. Available at http://www.ncbi.nlm.nih.gov/pubmed/17159659.
- Vannappagari V, et al. Zidovudine exposure during pregnancy and hypospadias in infants: data from the antiretroviral pregnancy registry, 1989-2011. Abstract no. MOPE070. Presented at: 19th International AIDS Conference. 2012.
- Williams PL, Crain M, Yildirim C, et al. Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants. JAMA Pediatr. 2015;169(1):45-55. Available at http://www.ncbi.nlm.nih.gov/pubmed/25383770.
- Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989–31 January 2017. 2017. Available at www.APRegistry.com.
- 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.
- Vannappagari V, Albano JD, Koram N, Tilson H, Scheuerle AE, Napier MD. Prenatal exposure to zidovudine and risk for ventricular septal defects and congenital heart defects: data from the Antiretroviral Pregnancy Registry. Eur J Obstet Gynecol Reprod Biol. 2016;197:6-10. Available at http://www.ncbi.nlm.nih.gov/pubmed/26687320.
- 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.
- Garcia-Otero L, Lopez M, Gomez O, et al. Zidovudine treatment in HIV-infected pregnant women is associated with fetal cardiac remodelling. AIDS. 2016;30(9):1393-1401. Available at https://www.ncbi.nlm.nih.gov/pubmed/26919731.
- Culnane M, Fowler M, Lee SS, et al. Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams. JAMA. 1999;281(2):151-157. Available at http://www.ncbi.nlm.nih.gov/pubmed/9917118.
- Hanson IC, Antonelli TA, Sperling RS, et al. Lack of tumors in infants with perinatal HIV-1 exposure and fetal/neonatal exposure to zidovudine. J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20(5):463-467. Available at http://www.ncbi.nlm.nih.gov/pubmed/10225228.
- Ivy W, 3rd, Nesheim SR, Paul SM, et al. Cancer among children with perinatal exposure to HIV and antiretroviral medications—New Jersey, 1995-2010. J Acquir Immune Defic Syndr. 2015;70(1):62-66. Available at https://www.ncbi.nlm.nih.gov/pubmed/26017660.
- Hankin C, Lyall H, Peckham C, Tookey P. Monitoring death and cancer in children born to HIV-infected women in England and Wales: use of HIV surveillance and national routine data. AIDS. 2007;21(7):867-869. Available at http://www.ncbi.nlm.nih.gov/pubmed/17415042.
- Bardeguez AD, Shapiro DE, Mofenson LM, et al. Effect of cessation of zidovudine prophylaxis to reduce vertical transmission on maternal HIV disease progression and survival. J Acquir Immune Defic Syndr. 2003;32(2):170-181. Available at http://www.ncbi.nlm.nih.gov/pubmed/12571527.
- 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.
- Van Dyke RB, Chadwick EG, Hazra R, Williams PL, Seage GR 3rd. The PHACS SMARTT Study: assessment of the safety of in utero exposure to antiretroviral drugs. Front Immunol. 2016;7:199. Available at https://www.ncbi.nlm.nih.gov/pubmed/27242802.