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
Didanosine (Videx, ddI)
(Last updated:3/28/2014; last reviewed:3/28/2014)
Didanosine is classified as FDA Pregnancy Category B.
Animal Carcinogenicity Studies
Didanosine is both mutagenic and clastogenic in several in vitro
and in vivo
assays. Long-term animal carcinogenicity screening studies at human exposures of 0.7 to 1.7 times in mice and 3 times in rats have been negative.
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.
No evidence of teratogenicity or toxicity was observed with administration of didanosine at 12 and 14 times human exposure, respectively, in pregnant rats and rabbits. Among cases of first-trimester didanosine exposure reported to the Antiretroviral Pregnancy Registry, prevalence of birth defects was 4.8% (20 of 413 births; 95% CI, 3.0%–7.4%) compared with 2.7% in the U.S. population, based on Centers for Disease Control and Prevention surveillance.1
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.
Placental and Breast Milk Passage
Placental transfer of didanosine was low-moderate in a Phase I/II safety and pharmacokinetic (PK) study.2
This was confirmed in a study of 100 HIV-infected pregnant women who were receiving nucleoside reverse transcriptase inhibitors (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) and in 15 of 24 (62%) samples, cord blood concentrations for didanosine were below the limits of detection.3
A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. It is not known if didanosine is excreted in human breast milk.
Human Studies in Pregnancy
A Phase I study (PACTG 249) of didanosine was conducted in 14 HIV-infected pregnant women 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. PK parameters after oral administration were not significantly affected by pregnancy, and dose modification from the usual adult dosage is not needed.
Lactic acidosis, fatal in some cases, has been described in pregnant women receiving the combination of didanosine and stavudine along with other ARV agents;4-6
the Food and Drug Administration 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. These two drugs should be prescribed together to pregnant women only when the potential benefit clearly outweighs the potential risk. Clinicians should prescribe this ARV combination in pregnancy with caution and generally only when other nucleoside analog drug combinations have failed or have caused unacceptable toxicity or side effects.
- Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 Jan 1989–31 July 2013. 2013. Available at http://www.APRegistry.com. Accessed March 5, 2014.
- 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.
- 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.
- 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.
- 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.
- Bristol-Myers Squibb Company. Healthcare Provider Important Drug Warning Letter. January 5, 2001. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm173947.htm. Accessed on February 14, 2014.