Perinatal Exposure to Antiretroviral Agents: Risks and Benefits

In the United States, approximately 7000 infants are born to HIV-infected women each year. Before 1994, between 20% and 30% of these infants became infected with HIV and developed a chronic HIV infection with a shortened life expectancy. In 1994, results of a multicenter Pediatric AIDS Clinical Trials Group placebo-controlled study of zidovudine given during pregnancy, labor and delivery and to the infant for 6 weeks showed reduction of perinatal transmission of HIV by 67% (1). Following the release of these study results, the U.S. Public Health Service (USPHS) Task Force recommended the use of zidovudine during pregnancy for reduction of perinatal transmission (2). The USPHS Task Force no longer recommends monotherapy as optimal treatment for HIV infection, but continues to include zidovudine as a part of combination antiretroviral therapy given to women during pregnancy both for their own health and for reduction of perinatal transmission (3). This approach has been extremely successful and has reduced perinatal transmission of HIV in the United States to between 1% and 4% (4, 5). This decrease in perinatal transmission of HIV has also resulted in a 66% reduction in the number of cases of pediatric AIDS reported in the United States between 1993 and 1997 (6).

In addition, short-course zidovudine alone or in combination with lamivudine has been successful in decreasing perinatal transmission by 40–50% in developing countries (7–9). This success in preventing HIV infection in thousands of infants is, however, also associated with the risk of exposure to drugs with unknown long-term toxic effects. Short-term studies in the United States and Europe of cohorts of infants who were exposed to zidovudine have been reassuring, with no increase in congenital anomalies, cancer incidence, or preterm delivery compared with unexposed controls. There were also no significant differences in immunologic parameters, growth, or neurodevelopment (10–13).

In 1999, however, Blanche et al (14) reported mitochondrial dysfunction in eight of 1754 infants who had been exposed to nucleoside analogues including zidovudine (ZDV) and lamivudine (3TC) in utero or post partum. Two of these infants developed serious neurologic disease and subsequently died. This prompted investigators to look for similar cases in HIV-exposed but uninfected infants. Mitochondrial toxicity in children may be manifested as skeletal muscle and cardiac muscle changes, lactic acidosis, progressive neurologic disease, growth failure and liver, kidney or pancreatic disease (15). The French Perinatal Cohort Study group evaluated 2644 HIV-negative children exposed to antiretrovirals for symptoms compatible with mitochondrial dysfunction. Twelve children were symptomatic: 10/12 had abnormal MR images, 7/12 had an episode of hyperlactemia, and 11/12 had a profound deficit in one of the respiratory chain complexes. This represents an 18-month incidence for neuromitochondrial disease of 0.26% compared with 0.01% in the general population (16). A large retrospective study undertaken by the Perinatal Safety Review Working Group evaluated five large cohorts of infants in the United States comprising more than 20,000 children, half of whom had been exposed to antiretroviral agents: 223 deaths occurring in children less than 60 months of age were reviewed, and evidence for mitochondrial dysfunction as a factor in these deaths could not be established (17). A prospective study of echocardiograms obtained over the first 5 years of life from 382 HIV-negative children born to HIV-infected women did not show evidence for mitochondrial toxicity (18).

There is ample evidence in the literature for mitochondrial dysfunction induced by nucleoside analogues. Although these drugs inhibit the viral reverse transcriptase, they can also inhibit other DNA polymerases, including mtDNA polymerase gamma. Inhibition of this enzyme can result in depletion of the mitochondrial DNA (mtDNA) and mitochondrial dysfunction (19). Gerschenson et al (20, 21) demonstrated fetal mitochondrial heart and skeletal muscle damage in Erythrocebus patas monkeys exposed in utero to ZDV alone or in combination with 3TC. Poirier et al (22) studied three groups of uninfected infants for markers of mitochondrial toxicity; those born to HIV-negative women (n = 30) and those born to HIV infected women (n = 20) who either received no antiretroviral therapy (n = 10) or zidovudine during pregnancy (n = 10). This study demonstrated that zidovudine causes depletion in mtDNA in infants that can persist up to 2 years. Alimenti et al (23) prospectively measured plasma lactate in a group of 38 HIV-negative infants exposed to antiretroviral therapy to investigate the incidence of potential mitochondrial toxicity. Plasma lactate was elevated on at least one determination in 35/38 children followed over the first 6 months of life, with 10 having higher levels (>5 mmol/L). The clinical significance of these findings is uncertain.

In this issue of the AJNR, Blanche et al describe a cohort of 49 infants exposed in utero and perinatally to antiretroviral agents for reduction of HIV transmission from mother to infant. None of the infants was infected with HIV. All the infants received treatment with nucleoside reverse transcriptase inhibitors in the postpartum period. Of these, 49 received zidovudine and 34 received zidovudine in addition to lamivudine. Seventeen of these children had exposure to other antiretroviral agents that were not specified. Twenty-two children had evidence for mitochondrial dysfunction, with 18 having neurologic symptoms. Twenty-seven children had no known mitochondrial dysfunction, and of them 14 had neurologic symptoms similar to those found in the group with mitochondrial dysfunction. Seven had persistent biochemical abnormalities by laboratory testing, and six were asymptomatic. MR imaging showed abnormalities of the brain in all but six of the children with mitochondrial abnormalities; in the 27 infants with no mitochondrial dysfunction, eight showed MR imaging abnormalities. It will be important to follow up these children to determine the long-term significance of these MR imaging abnormalities. The findings in this study suggest that some infants exposed to antiretroviral agents including zidovudine and lamivudine may develop mitochondrial toxicity and resultant neurologic or neurodevelopmental abnormalities.

These findings emphasize the importance of both short-term and long-term follow-up for infants exposed to antiretroviral therapy. In the United States, the Pediatric AIDS Clinical Trials Group funded through the National Institutes of Health has established a long-term follow-up protocol that includes both infected and uninfected children exposed to antiretroviral agents in utero. These children have been followed up since the opening of this protocol in 1993, and new infants continue to be accrued into this study. After 1994, women were offered monotherapy with zidovudine for reduction of perinatal transmission (2). With the introduction of newer antiretroviral agents, however, drugs acting at different points in the HIV replicative cycle are being used in combination and include nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors. Thus, continued follow-up of infants exposed to antiretroviral agents is imperative.

At present, serious neurologic toxicity has been reported in small numbers of infants exposed to zidovudine or lamivudine. There is an emerging database of information regarding mitochondrial dysfunction in HIV-negative, antiretroviral-exposed infants. There is immediate need for prospective, controlled studies of HIV-exposed infants with the goal of better defining toxicities, including mitochondrial abnormalities, their incidence, and their long-term consequences. If abnormalities occur, are they transient or will they persist, possibly resulting in long-term effects? Elective caesarian section is another technique that reduces the risk of perinatal transmission and is routinely offered to women in the United States whose viral load is greater than 1000 copies/mL at the time of delivery (24, 25). Current recommendations for the treatment of the pregnant woman with HIV infection include combination therapy using at least three drugs (3). Women with low (<1000 RNA copies/mL) or undetectable viral loads in their plasma have a very low risk of perinatal transmission of HIV (26). This raises the question of whether infants born to women with a very low or undetectable viral load need 6 weeks of treatment after delivery for prevention of HIV, or could this course be shortened, thus decreasing exposure to these agents? A combined intervention similar to that used for prevention of hepatitis B infection in neonates whose mothers are infected with hepatitis B by using hyperimmune immunoglobulin along with vaccine at birth may be useful in HIV as well (27, 28). HIV hyperimmune immunoglobulin or monoclonal antibodies directed against HIV proteins given at birth along with an HIV vaccine, once such a vaccine is available, might be an alternative effective strategy. It is imperative that research dollars be available to answer these important questions. We have made significant strides in prevention of perinatal transmission of HIV, but this must be accomplished by using the safest, most efficacious methods available.

It is important to weigh the benefits of antiretroviral therapy against the risk of an adverse event occurring in the woman, the fetus, or the neonate. Worldwide, about 600,000 perinatal HIV infections occur yearly. Use of simple short-course therapeutic regimens in developing countries can prevent between 40–50% of these cases. Dr. Lynne Mofenson of the National Child Institute of Health and Child Development stated in an editorial, “Given the fatal nature of HIV infection, any long-term risk entailed by the in utero or neonatal exposure of children to antiretroviral drugs would have to be profound, occur early in life, and occur in a substantial proportion of those exposed to outweigh the proved benefit of antiretroviral prophylaxis in reducing perinatal transmission of HIV”. Current information does not seem to justify changing current recommendations for reduction of perinatal transmission of HIV. Further research to define the spectrum of toxicities and to better understand the mechanism of the mitochondrial effects of these drugs is, however, essential.

• American Society of Neuroradiology