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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
Zidovudine (Retrovir, AZT, ZDV)
(Last updated: August 6, 2015; last reviewed: August 6, 2015)
Zidovudine is classified as Food and Drug Administration Pregnancy Category C.
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.1 In mice, seven 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, two 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.
Two transplacental carcinogenicity studies were conducted in mice.2,3 In one 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.3 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.2 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.4
Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity, as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one-half of the daily dose) in rats 66 to 226 times and in rabbits 12 to 87 times mean steady-state peak human plasma concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose of 3,000 mg/kg/day (very near the oral median lethal dose in rats of 3,683 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.
Increased fetal resorption occurred in pregnant rats and rabbits treated with zidovudine doses that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100-mg dose of zidovudine. No other developmental anomalies were reported. In another developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily AUC in humans given 600 mg/day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one-fifth the lethal dose.
Human Studies in Pregnancy
Zidovudine pharmacokinetics are not significantly altered by pregnancy, and standard adult doses are recommended.5,6
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 1.5.7 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 the nursing infants, who received zidovudine only via breast milk.8-10
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.5,11 Similarly, no increase in birth defects was detected among infants enrolled in the large observational cohorts PACTG 219/219C and P1025.12,13 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.14,15 The French Perinatal Cohort reported that first-trimester zidovudine exposure was associated with congenital heart defects (2.3%, or 74/3,267; adjusted odds ratio = 2.2 [95% confidence interval (CI), 1.3–3.7]).16 In the PHACS/SMARTT cohort, there was no association between first-trimester exposure and congenital anomalies.17 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 genitourinary system. No such increase in birth defects has been observed with zidovudine. With first-trimester zidovudine exposure, the prevalence of birth defects was 3.2% (129 of 4,034 births; 95% CI, 2.7%–3.8%), compared with a total prevalence in the U.S. population of 2.7%, based on Centers for Disease Control and Prevention surveillance.18
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,19 in prospective cohort studies,20 and in matches between HIV surveillance and cancer registries.21,22
Other Safety Data
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.23
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.11,19
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.
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. J Natl Cancer Inst. 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.
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;19(6):587-595. 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, al e. 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.
Sibiude J, Mandelbrot L, Blanche S, et al. Association between prenatal exposure to antiretroviral therapy and birth defects: an analysis of the French perinatal cohort study (ANRS CO1/CO11). PLoS Med. 2014;11(4):e1001635. Available at http://www.ncbi.nlm.nih.gov/pubmed/24781315.
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 Jan 1989 - 31 July 2014. Wilmington, NC: Registry Coordinating Center. 2014. Available at http://www.APRegistry.com.
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.
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.
Ivy W, Nesheim SR, Paul S, et al. Cancer among children with perinatal exposure to HIV and antiretroviral medications—New Jersey, 1995-2010. In press.
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.