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

Archived Drugs

Didanosine (Videx, ddI)

Didanosine is classified as Food and Drug Administration (FDA) Pregnancy Category B.¹

Didanosine is not recommended for use in pregnant women with HIV due to its toxicity.

Animal Studies

Carcinogenicity
Didanosine is both mutagenic and clastogenic in several in vitro and in vivo assays. Long-term animal carcinogenicity screening studies of 0.7 times to 1.7 times human exposure in mice and 3 times human exposure in rats have been negative.¹

Reproduction/Fertility
At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid and late lactation. These rats showed reduced food intake and body weight gains; however, the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation.

Teratogenicity/Adverse Pregnancy Outcomes
No evidence of teratogenicity or toxicity was observed in pregnant rats and rabbits with exposures of didanosine that were 12 times and 14 times, respectively, the exposures seen in humans.

Placental and Breast Milk Passage
A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta.

Human Studies in Pregnancy

Pharmacokinetics
A Phase 1 study (PACTG 249) of didanosine was conducted in 14 pregnant women with HIV who were enrolled at gestational age 26 to 36 weeks and treated through 6 weeks postpartum.² The drug was well tolerated during pregnancy by the women and the fetuses. Pharmacokinetic (PK) parameters after oral administration were not significantly affected by pregnancy, and dose modification from the usual adult dosage is not needed.

Placental and Breast Milk Passage
Placental transfer of didanosine was low-moderate in a Phase 1/2 safety and PK study.² This was confirmed in a study of 100 pregnant women with HIV who were receiving nucleoside reverse transcriptase inhibitors (NRTIs), generally as part of a two- or three-drug combination antiretroviral (ARV) regimen. At the time of delivery, cord-to-maternal-blood ratio for didanosine (n = 10) was 0.38 (range 0.0–2.0). In 15 of 24 samples (62%), cord blood concentrations for didanosine were below the limits of detection.³

It is not known whether didanosine is excreted in human breast milk.

Teratogenicity/Adverse Pregnancy Outcomes
The French Perinatal Cohort reported that head and neck birth defects were associated with first-trimester exposure to didanosine (0.5%, adjusted odds ratio [aOR] 3.4, 95% CI, 1.1–10.4, P = 0.04).⁴ Though the PHACS/SMARTT cohort found no association between any individual NRTIs and birth defects, after adjusting for birth cohort and other factors, didanosine administered in combination with stavudine was associated with an overall increase in congenital abnormalities;⁵ it should be noted that the combination of didanosine and stavudine should not be used in pregnant women with HIV (or anyone with HIV) because of a higher risk of toxicity. Among 897 births to women with HIV in a Spanish cohort, there was no significant difference between the rate of birth defects after first-trimester exposure and the rate of birth defects after second- and third-trimester exposure (odds ratio [OR] 0.61, 95% CI, 0.16–2.27).⁶ In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to didanosine in humans have been monitored to be able to detect at least a 2-fold increase in the risk of overall birth defects.⁷ Among cases of first-trimester didanosine exposure reported to the Antiretroviral Pregnancy Registry, prevalence of birth defects was 4.68% (20 of 427 births; 95% CI, 2.88% to 7.14%) compared with 2.72% in the U.S. population, based on Centers for Disease Control and Prevention surveillance.⁷ All defects were reviewed in detail by the Registry, and no pattern of defects was discovered. The rate and types of defects will continue to be closely monitored.

Safety
Lactic acidosis, fatal in some cases, has been described in pregnant women receiving the combination of didanosine and stavudine along with other ARV agents;^8-10 the FDA and Bristol-Myers Squibb have issued a warning to health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed didanosine and stavudine in combination.

The PHACS/SMARTT cohort found that after adjusting for birth cohort and other factors, didanosine administered in combination with stavudine was associated with the occurrence of neurodevelopmental disability. However, there was no increase in the likelihood of adverse events in the following domains with didanosine alone: metabolic, growth and development, cardiac, neurological, neurodevelopmental, behavior, language, and hearing.^11,12 As noted above, the combination of didanosine and stavudine should not be used in pregnant women with HIV (or anyone with HIV) because of a high risk of toxicity.

In a multivariate analysis of the association between in utero ARV exposure and risk of cancer in HIV-exposed, uninfected infants, the French Perinatal Study reported a 5.5-fold (95% CI, 2.1–14.4) increase in cancer incidence with first-trimester didanosine exposure.¹³

References

1. Didanosine [package insert]. Food and Drug Administration. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021183s028lbl.pdf.
2. Wang Y, Livingston E, Patil S, et al. Pharmacokinetics of didanosine in antepartum and postpartum human immunodeficiency virus-infected pregnant women and their neonates: an AIDS clinical trials group study. J Infect Dis. 1999;180(5):1536-1541. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10515813.
3. 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.
4. 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.
5. Williams PL, Crain M, Yildirim C, et al. Congenital anomalies and in utero antiretroviral exposure in HIV-exposed uninfected infants. JAMA. 2015. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286442/.
6. 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.
7. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report 1 January 1989–31 January 2018. Wilmington, NC: Registry Coordinating Center. 2018. Available at: http://www.apregistry.com/.
8. Mandelbrot L, Kermarrec N, Marcollet A, et al. Case report: nucleoside analogue-induced lactic acidosis in the third trimester of pregnancy. AIDS. 2003;17(2):272-273. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12545093.
9. Sarner L, Fakoya A. Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy in HIV-1 positive women taking antiretroviral medication. Sex Transm Infect. 2002;78(1):58-59. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11872862.
10. Bristol-Myers Squibb Company. Healthcare provider important drug warning letter. 2001. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/21183s1ltr.pdf
11. 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.
12. 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.
13. Hleyhel M, Goujon S, Delteil C, et al. Risk of cancer in children exposed to didanosine in utero. AIDS. 2016;30(8):1245-1256. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26854809.