Incorporation of zidovudine into leukocyte DNA from HIV-1-positive adults and pregnant women, and cord blood from infants exposed in utero

Objective: The nucleoside analog 3'-azido-3'-deoxythymidine (ZDV) has wides pread clinical use but also is carcinogenic in newborn mice exposed to the drug in utero and becomes incorporated into newborn mouse DNA. This pilot s tudy was designed to determine ZDV incorporation into human blood cell DNA from adults and newborn infants. Design: in this prospective cohort study, peripheral brood mononuclear cell s (PBMC) were obtained from 28 non-pregnant adults and 12 pregnant women gi ven ZDV therapy, six non-pregnant adults with no exposure to ZDV, and six n on-pregnant adults who last received ZDV greater than or equal to 6 months previously. In addition, cord blood leukocytes were obtained from 22 infant s of HIV-1-positive, ZDV-exposed women and from 12 infants unexposed to ZDV . There were 11 mother-infant pairs involving HIV-1-positive women. Methods: DNA was extracted from PBMC obtained from non-pregnant HIV-1-posit ive adults taking ZDV, pregnant HIV-1-positive women given ZDV during pregn ancy, and from adults not taking ZDV. Cord blood leukocytes were examined f rom infants exposed to ZDV in utero and from unexposed controls. DNA sample s were assayed for ZDV incorporation by anti-ZDV radioimmunoassay (RIA). Results: The majority (76%) of samples from ZDV-exposed individuals, pregna nt women (8 of 12), non-pregnant adults (24 of 28), or infants at delivery (15 of 22), had detectable ZDV-DNA levels. The range of positive values far ZDV-treated adults and infants was 25-544 and 22-452 molecules ZDV/10(6) n ucleotides, respectively. Analysis of 11 mother-infant pairs showed variabl e ZDV-DNA incorporation in both, with no correlation by pair or by duration of drug treatment during pregnancy. Two of the 24 samples from individuals designated as controls were positive by anti-ZDV RIA. The 20-fold range fo r ZDV-DNA values in both adults and infants suggested large interindividual differences in ZDV phosphorylation. Conclusions: Incorporation of ZDV into DNA was detected in most of the samp les from ZDV-exposed adults and infants. Therefore, the biologic significan ce of ZDV-DNA damage and potential subsequent events, such as mutagenicity, should be Further investigated in large cohorts of HIV-positive individual s. The interindividual variability of ZDV incorporation into DNA in humans is considerable and consistent with reported variability in the formation o f the ZDV-trisphosphate, (C) 1999 Lippincott Williams & Wilkins.