Pharmacokinetics of didanosine and drug resistance mutations in infants exposed to zidovudine during gestation or postnatally and treated with didanosine or zidovudine in the first three months of life

Background: There are limited numbers of drugs that are available in formulations that are appropriate for neonates and few studies assessing resistance among infants born to human immunodeficiency virus (HlV)-infected women. Methods: Pharmacokinetics and tolerance of didanosine (ddI) were determined for infants ≤120 days of age. Infants received at least 24 hours of zidovudine (ZDV) treatment, followed by a single ddI dose and pharmacokinetic sampling. The target area under the concentration-time curve (AUC) was between 2.5 and 5.0 μM · hour. Toxicity and drug resistance mutations were assessed at baseline and follow-up times. Results: The initial ddI pharmacokinetic dosing of 50 mg/m² for infants >28 days of age achieved a median AUC_0-∞ of 2.8 μM · hour. For infants ≤28 days of age, the target AUC was achieved after dose escalation from 25 mg/m² (median AUC_0-∞, 1.4 μM · hour) to 50 mg/m² (median AUC_0-∞, 5.40 μM · hour). At baseline, 25% of infected infants had drug resistance mutations (9 of 44 to ZDV and 2 of 44 to ddI). Resistance mutations were present for 29% of infants (5 of 17 infants) with in utero ZDV exposure and 25% (8 of 32 infants) with prior ZDV treatment. The most common ZDV mutation noted at baseline was the T215Y/F (n = 7) mutation; 2 of these infants also had the M41L mutation, which is associated with high level ZDV resistance. No prior exposure was noted for the 2 infants with ddI resistance, which indicates possible perinatal transmission of ddI-resistant virus to these infants. Conclusions: A dose of 50 mg/m² is the appropriate ddI dose for infants <120 days of age and is a safe treatment for newborns when used in combination with ZDV. Genotypic resistance occurs frequently among infected infants exposed to ZDV during gestation or postnatally, which suggests that resistance testing should be considered for infants with newly diagnosed HIV infection.