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Vertical Transmission

Spring 1999

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

Ever since the results of the ACTG 076 trial were published in 1993, AZT (Retrovir®) has been administered to HIV-infected pregnant women and their infants to reduce the rate of mother-to-child transmission. In the era of HAART, many doctors and scientists are asking whether combination therapies might not prove to be even more effective than AZT alone, but without reliable safety data on protease inhibitor use in pregnancy, some practitioners have been reluctant to advocate HAART for pregnant women.

At the 12th World AIDS Conference last year, a Swiss trial reported that there was a 33% risk of premature birth in pregnant women taking protease inhibitors (PIs), and a small but significant risk of brain hemorrhage in their infants. These findings led to a temporary freeze on all U.S. government-sponsored trials of HAART during pregnancy, but at the recent Sixth Retrovirus Conference in Chicago, several studies were presented which challenge the findings of the Swiss group.

Presented in Chicago

A large survey of 85 pregnant women across the country who were treated with various protease inhibitors reported a 20% premature birth rate. This is higher than for uninfected women, but the majority of those women who delivered prematurely had other risk factors, such as smoking, twin pregnancy, and previous premature deliveries. There were no significant adverse events in the infants, and, remarkably, no instances of transmission -- although to date, only half of the infants have been adequately evaluated.

Another survey from the University of Southern California reported on 64 women who took HAART during their pregnancies. Some of these women were on non-PI-containing regimens, and the overall risk of premature delivery was only 13%. To date, 47 of these mothers have delivered, and although four infants had birth defects, these defects were associated with other conditions such as Down syndrome or inherited disorders. More than half of the newborns had transient liver abnormalities, but once again there were no cases of HIV transmission.

Interim data from an ongoing French study in which both mothers and babies were treated with AZT and 3TC (Epivir®) were presented by Dr. Sebastian Blanche from the Hospital Necker in Paris. Their analysis of the first 200 women enrolled in the study showed an overall transmission rate of 2.6% compared with 6.5% for mothers and infants taking AZT alone. The combination was well tolerated, but almost 40% of the women developed 3TC-resistant virus after only a month of dual therapy.

"Despite lingering concerns over the long-term safety of in utero exposure to antiretrovirals, it's likely that combination therapy during pregnancy will become the rule rather than the exception."

A Disturbing Addendum

In a controversial and unexpected addition to their published abstract, Blanche and colleagues also reported the finding that two uninfected infants developed neurodegenerative disorders at four months of life. Both babies died a few months later, and muscle biopsies suggested that their mytochondria (cellular energy-making machinery) had been poisoned. In spite of an exhaustive investigation, no known disorders were identified to explain these two deaths, and they questioned whether this was a side effect of the AZT/3TC combination which the newborns had taken for six weeks. Other researchers cautioned against making such an assumption, pointing out that the same combination has been extensively used in young children and infants without this phenomenon having been observed before.

Overall, despite lingering concerns over the long-term safety of in utero exposure to antiretrovirals, with reported transmission rates consistently below 2%, it seems likely that combination therapy during pregnancy will become the rule rather than the exception. Will we ever be able to eradicate vertical transmission in the U.S.? Dr. Lynn Mofensen from the National Institutes of Health thinks not. Nationwide, about 15% of HIV-infected women receive no prenatal care. Most of these are young, minority women -- the same group with the fastest-growing rate of new HIV infections. Without improvements in the delivery of care to these women, transmission rates will remain much higher in this segment of the population.

Furthermore, as the prevalence of multidrug-resistant virus rises in this community, HAART may become less effective at preventing vertical transmission, and those infants that do become infected will be more likely to harbor hard-to-treat resistant viruses themselves. It would certainly be premature to suggest that these potential downsides may outweigh the remarkable benefits of HAART, but one group from North Carolina has already identified a baby who acquired multidrug-resistant virus from his mother and continued to develop more resistance mutations despite aggressive antiviral treatment. Is this a sign of things to come? CRIA Update will continue to follow this area.

The Role of Caesarean Section

In contrast to the Geneva AIDS Conference, there were few abstracts presented in Chicago that addressed the role of Caesarean section in reducing the rate of vertical transmission. However, the consensus appears to be that elective C-section is undoubtedly beneficial if AZT monotherapy is used as prophylaxis, or if the prenatal viral load is high. In these situations, elective C-section may reduce the transmission rate by more than 50%. However, the efficacy of C-section has not been proven in pregnant women who are well-controlled on HAART. These mothers already have a very low risk of transmission and it is not clear that a C-section would lower the risk further.

Two studies presented data on the complication rates of elective C-section in HIV-infected women. The first, a survey of modes of delivery among 1,112 women enrolled into the Women and Infant Transmission Study, found that women who had C-sections stayed twice as long in the hospital and had three to four times the post-delivery complications than did the women who gave birth vaginally. The second study -- of 497 HIV-infected pregnant women with CD4 counts below 500 -- showed an equally striking difference between surgical and natural childbirth. There were almost four times as many uterine infections in the mothers who had C-sections than in those who did not. If the number of HIV-infected pregnant women having elective C-sections increases, then there is likely to be an increase in the number of post-operative complications. The study authors highlighted the importance of evaluating every patient individually to determine the balance of risk and benefit in each case, rather than performing C-sections on all mothers as a matter of routine.

Many Interventions, Little Access

An HIV-infected pregnant woman in the developed world can access a range of interventions to ensure that her child has a minimal risk of becoming infected. With some exceptions, most developing countries can offer none of these costly measures. In some parts of sub-Saharan Africa, where almost one quarter of all women of child-bearing age are HIV-positive, transmission rates are still in the range of 20-25%.

Research to find alternative therapeutic options in these countries has been slow coming, but Dr. Joseph Saba of the UNAIDS presented preliminary results from PETRA, a large trial of AZT and 3TC to prevent vertical transmission. The placebo-controlled study, which enrolled almost 1,800 pregnant women in South Africa, Tanzania and Uganda, evaluated three different therapeutic options against placebo -- AZT/3TC given to mothers and babies from 36 weeks gestation to one week after delivery; AZT/3TC given to mothers and babies from the onset of labor to a week after delivery; and AZT/3TC given only during labor.

The placebo group transmission rate was 17.2% -- no different than that for mothers receiving treatment only during the labor. The most intensive regimen was most effective, producing a transmission rate of 8.6%, but a course of only one week of treatment to mother and child from the onset of labor produced a rate of 10.8% -- a significant 37% reduction in the risk of transmission. The study had previously come under much criticism from consumer advocacy groups that had challenged the rationale for inclusion of a placebo group, arguing that since the benefits of therapy are well established, it was unethical to treat patients with placebos. Dr. Saba pointed out that without a placebo group, it would have been impossible to determine that treatment during labor alone was ineffective.

These transmission results were based on samples taken at six weeks of life, and might not include some of the infants infected after birth by breast feeding. The completed analysis will provide a more accurate measure of the usefulness of this short-course regimen as a relatively cost-effective method of reducing transmission in breastfeeding HIV-positive mothers.

Balancing Research and Ethics

Another study from Thailand using monotherapy with Norvir® (ritonavir) from the 36th week of pregnancy also reduced the transmission rate to just below 10 percent. However, even the proponents of these short-course regimens concede that, for the most part, they are economically unfeasible in the developing world. Dr. Catherine Wilfert from Duke University addressed the need to test alternative modalities in an appropriate ethical context. She presented the consensus of an international group that was convened to discuss the ethical principles which should govern such research in the developing world. Their guidelines boiled down to four essentials:

  • that the treatment should be safe and effective;

  • that there should be no obligation to provide the highest standard of care which is available anywhere in the world;

  • that it is acceptable to have a placebo group, provided the therapeutic modality being tested is other than an antiviral;

  • and that if an intervention is found to be effective, it should be implemented in that country on a wide scale as soon as possible.

Hopefully these guidelines will provide a boost to scientists and governments to investigate viable options such as protective vaccination of exposed newborns, cheaper antivirals, nutritional agents such as vitamin A and methods to cut down the risk of breastfeeding.

Dr. Shaffik Essajee is a pediatrician specializing in infectious diseases. He works in the pediatric HIV/AIDS clinic of Bellevue Hospital.

Back to the CRIA Update Spring 99 Contents Page.

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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This article was provided by AIDS Community Research Initiative of America. It is a part of the publication CRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
See Also
What Did You Expect While You Were Expecting?
HIV/AIDS Resource Center for Women
More Research on Pregnancy and HIV/AIDS