Elsevier

The Lancet

Volume 354, Issue 9184, 25 September 1999, Pages 1084-1089
The Lancet

Early Report
Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues

https://doi.org/10.1016/S0140-6736(99)07219-0Get rights and content

Summary

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.

Findings

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.

Interpretation

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.

Introduction

The antiretroviral nucleoside analogue zidovudine can lower the rate of mother-to-child transmission of HIV-1 infection.1 Official recommendations to use this preventive treatment during the second half of pregnancy, labour, and for the first 6 weeks of life in neonates2 have led to a substantial decrease in the number of infected children in more-developed countries.3, 4 Simplified regimens adapted to the medical and economic conditions in Africa and South Asia have also been effective.5

Tolerance of this treatment has been a concern.6, 7, 8 The data from the first protocol9 and later observational studies were reassuring. The most common secondary effect was, as expected, transient and rarely severe macrocytic anaemia. Whether late side-effects appear after the period during which children are not infected by HIV-1 is not clear. This question prompted long-term follow-up studies10 and the establishment of national registers for antiretroviral prescriptions during pregnancy. The development of multidrug antiretroviral therapies reinforces the need for such studies because many HIV-1-infected women have received zidovudine in combination with other nucleoside analogues, especially lamivudine, since 1995. We report mitochondrial dysfunction in unrelated children, free of HIV-1 infection, exposed in utero and postnatally to one or two nucleoside analogues.

Section snippets

Patients

The French National Epidemiological Network for studying mother-to-child transmission of HIV-1 (Enquête Périnatale Francaise) is an epidemiological survey that was started in 1986 and involves more than 90 obstetrics and paediatrics centres throughout France. All participating centres adhere to a common monitoring schedule and include all seropositive women who agree to participate. By Jan 15, 1999, 3779 mother-child pairs were included, of which 1754 were exposed to zidovudine or other drugs

Patients

Eight children with mitochondrial dysfunction were found. The first two patients were identified by the analysis for serious adverse events of ANRS075. The other six patients were identified during continuing retrospective screening for mitochondrial symptoms among patients enrolled in the national epidemiological survey since 1986 and in the therapeutic trial (table 1).

At age 4·5 months, the first patient presented with visual impairment. Cerebral nuclear magnetic resonance imaging showed

Discussion

The clinical and biological symptoms of these eight children, and especially the persistently increased blood lactate concentrations in five of them, are compatible with mitochondrial respiratory-chain dysfunction. This diagnosis is supported by specific tissue and cell mitochondrial analyses. Caution is required in interpretation of the enzymology results because of the variations in control populations. We took only values substantially different from normal to be informative. We used ratios

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