Cardiac Mitochondrial Compromise in 1-Yr-Old Erythrocebus patas Monkeys Perinatally- Exposed to Nucleoside Reverse Transcriptase Inhibitors

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Abstract
Hearts from 1-yr-old Erythrocebus patas monkeys were examined after in utero and 6-wk-postbirth exposure to antiretroviral nucleoside reverse transcriptase inhibitors (NRTIs). Protocols were modeled on those given to human immunodeficiency virus (HIV)-1-infected pregnant women. NRTIs were administered daily to the dams for the last 20% or 50% of gestation, and to the infants for 6 wk after birth. Exposures included: no drug (n=4); Zidovudine, 3′-azido-3′-deoxythymidine (AZT; n=4); AZT/Lamivudine, (−)-β-l-2′, 3′-Dideoxy-3′-thiacytidine (Epivir, 3TC) (n=4); AZT/Didanosine (Videx, ddl) (n=4); and Stavudine (Zerit, d4T)/3TC (n=4). Echocardiograms and clinical chemistry showed no drug-related changes, but the d4T/3TC-exposed fetuses at 6 and 12 mo had increased white cell counts (ppp<0.05) in hearts of all NRTI-exposed monkeys in the following order: control < d4T/3TC<AZT<AZT/3TC<AZT/ddl. The clinical status of NRTI-exposed infants, as evidenced by behavior, clinical chemistry, OXPHOS activity and echocardiogram, was normal. However, extensive mitochondrial damage with clusters of similar-appearing damaged heart mitochondria observed by electron microscopy, and an increase in mtDNA quantity, that persisted at 1 yr of age, suggest the potential for cardiotoxicity later in life.

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