Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States

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Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors

Didanosine (Videx, ddI)

Last Updated: November 14, 2017; Last Reviewed: November 14, 2017

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

Animal Studies

Carcinogenicity Studies
Didanosine is both mutagenic and clastogenic in several in vitro and in vivo assays. Long-term animal carcinogenicity screening studies of 0.7 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.

Adverse Pregnancy Outcomes
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.

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 I study (PACTG 249) of didanosine was conducted in 14 pregnant women with HIV 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 I/II 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) and in 15 of 24 (62%) samples, cord blood concentrations for didanosine were below the limits of detection.3

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

Adverse Pregnancy Outcomes
The French Perinatal Cohort reported an association of head and neck birth defects with first-trimester exposure to didanosine (0.5%, 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 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 no longer be used in pregnant women with HIV (or anyone with HIV) because of higher risk of toxicity. Among 897 births to women with HIV in a Spanish cohort, there was no significant difference in the rate of birth defects between first-trimester compared to the second- and third-trimester exposure (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 4.74% (20 of 422 births; 95% CI, 2.91% to 7.23%) compared with 2.73% 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 in combination with stavudine was associated with 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 no longer be used in pregnant women with HIV (or anyone with HIV) because of higher risk of toxicity.

In a multivariate analysis of the association of 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

Excerpt from Table 9a
Generic Name
(Abbreviation)
Trade Name
Formulation Dosing Recommendations Use in Pregnancy
Didanosine
(ddI)
Videx
Videx EC

ddI (Videx)
Buffered Tablets (Non-EC):
  • No longer available
Solution:
  • 10 mg/mL oral solution

Videx EC (EC Beadlets) Capsules:
  • 125 mg
  • 200 mg
  • 250 mg
  • 400 mg


Generic Delayed-Release Capsules:
  • 200 mg
  • 250 mg
  • 400 mg
Standard Adult Doses
Body Weight ≥60 kg:
  • 400 mg once daily
With TDF:
  • 250 mg once daily; take 1/2 hour before or 2 hours after a meal.
Body Weight <60kg:
  • 250 mg once daily
With TDF:
  • 200 mg once daily; take 1/2 hour before or 2 hours after a meal.
Note: Preferred dosing with oral solution is twice daily (total daily dose divided into 2 doses); take 1/2 hour before or 2 hours after a meal.

PK in Pregnancy:
  • PK not significantly altered in pregnancy.
Dosing in Pregnancy:
  • No change in dose indicated.
Low-moderate placental transfer to fetus.b

In the APR, an increased rate of birth defects with ddI compared to general population was noted after both first-trimester (20/423, 4.7%; 95% CI, 2.9% to 7.2%) and later exposure (20/461, 4.3%; 95% CI, 2.7% to 6.6%). No specific pattern of defects was noted, and clinical relevance is uncertain.

ddI should not be used with d4T. Lactic acidosis, sometimes fatal, has been reported in pregnant women receiving ddI and d4T together.
a Individual antiretroviral 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:
          High: >0.6
          Moderate: 0.3–0.6
          Low: <0.3
c See Teratogenicity section for discussion of EFV and risks in pregnancy.
d Only indicated for use in chronic hepatitis B virus infection in adults
e Generic formulation available

Key to Acronyms: APR = Antiretroviral Pregnancy Registry; CI = confidence interval; d4T = stavudine; ddI = didanosine; EC = enteric coated; PK = pharmacokinetic

References

  1. Videx (didanosine) [package insert]. Bristol-Myers Squibb. 2015. Available at http://packageinserts.bms.com/pi/pi_videx_ec.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. In press. JAMA. 2014. Available at
  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 Infectious Diseases. 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 for 1 January 1989–1 January 2016. Wilmington, NC: Registry Coordinating Center. 2016.
  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. January 5, 2001. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm173947.htm. Accessed on October 25, 2017.
  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.

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