Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues.
BACKGROUND
Zidovudine is commonly administered during pregnancy to prevent mother-to-child HIV-1 transmission. We investigated mitochondrial toxic effects in children exposed to zidovudine in utero and after birth.


METHODS
We analysed observations of a trial of tolerance of combined zidovudine and lamivudine and preliminary results of a continuing retrospective analysis of clinical and biological symptoms of mitochondrial dysfunction in children born to HIV-1-infected women in France. Mitochondrial dysfunction was studied by spectrophotometry and polarography of respiratory-chain complexes in various tissues.


RESULTS
Eight children had mitochondrial dysfunction. Five, of whom two died, presented with delayed neurological symptoms and three were symptom-free but had severe biological or neurological abnormalities. Four of these children had been exposed to combined zidovudine and lamivudine, and four to zidovudine alone. No child was infected with HIV-1. All children had abnormally low absolute or relative activities of respiratory-chain complexes I, IV, or both months or years after the end of antiretroviral treatment. No mutation currently associated with constitutional disease was detected in any patient.


CONCLUSIONS
Our findings support the hypothesis of a link between mitochondrial dysfunction and the perinatal administration of prophylactic nucleoside analogues. Current recommendations for zidovudine monotherapy should however be maintained. Further assessment of the toxic effects of these drugs is required.
Blanche
S
S
Service d'Immunologie Hématologie Pédiatrique and INSERM U429 Laboratory, Hôpital Necker, Paris, France. stephane.blanche@nck.ap-hop-paris.fr
Tardieu
M
M
Rustin
P
P
Slama
A
A
Barret
B
B
Firtion
G
G
Ciraru-Vigneron
N
N
Lacroix
C
C
Rouzioux
C
C
Mandelbrot
L
L
Desguerre
I
I
Rötig
A
A
Mayaux
M J
MJ
Delfraissy
J F
JF
D000140:Acidosis, Lactic / Q000139:chemically induced; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000187:drug effects; D005260:Female; D005602:France / Q000453:epidemiology; D015658:HIV Infections / Q000453:epidemiology / Q000517:prevention & control*; D015497:HIV-1; D006801:Humans; D007223:Infant; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D019259:Lamivudine / Q000008:administration & dosage / Q000009:adverse effects*; D008431:Maternal-Fetal Exchange; D017237:Mitochondrial Encephalomyopathies / Q000139:chemically induced* / Q000453:epidemiology / Q000401:mortality / Q000503:physiopathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012016:Reference Values; D012189:Retrospective Studies; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects*
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D019259:Lamivudine; D015215:Zidovudine