Thai study success affects ongoing placebo trials

Results might be misinterpreted in U.S.

The success of the Thailand short-course zidovudine (AZT) trial in pregnant women will change the design of several placebo-controlled trials in the United States and abroad. While the trial’s findings affect developing countries the most, some health officials are concerned it will be misinterpreted as meaning the regimen used in the United States is overkill.

"I am concerned that the conclusion people will take from the Thai study is we don’t need to give the full 076 regimen, and I think if we do that we are going to see increases of transmission in the United States," warns Lynne Mofenson, MD, associate branch chief for clinical research at the Center for Research for Mothers and Children at the National Institute of Child Health and Human Development in Bethesda, MD.

The Centers for Disease Control and Prevention, which sponsored the Thailand study, stresses that the study was not designed to address perinatal prevention needs in the United States and other more industrialized countries where the 076 regimen is affordable. As a result, the study doesn’t change recommendations for perinatal HIV prevention in the United States, CDC officials say.

At the same time, however, the 076 study was designed nearly nine years ago, when very little was known about how HIV was transmitted from mother to child. It was thought then, for example, that about half of perinatal transmission occurred in utero. Consequently, the U.S. Food and Drug Administration insisted that AZT should be started after 14 weeks gestation, and a three-prong regimen was developed: treatment during pregnancy, intravenous treatment during labor, and postpartum treatment for the infant.

"Because we had never done a perinatal trial before, we didn’t feel like we had a lot of shots to determine effective prevention, so we put everything together we thought might be needed to get the best-shot type of approach and didn’t worry about which component was important," Mofenson explains.

Is the 076 regimen overdosed?

Consequently, the 076 trial could not tell researchers which component was most important to prevention. Now that a short-course trial giving a much small amount of drug appears to reduce the risk by 50% (compared to 70% for 076), the question raised is whether 076 is an overdosed regimen.

Mofenson, however, points to recent research indicating that much perinatal transmission takes place during labor and the period immediately after the child is born, when the mother’s infected cells are still living. "If the mother didn’t have any infected maternal cells, it might be a different story — maybe starting AZT at 14 weeks gestation might be overdoing it, maybe you could start later," she says. "But in essence I think it is a moot point for most women in the United States."

The reason is that with the new antiretroviral treatment guidelines for adults, most pregnant women in this country will be on antiretroviral therapy anyway for their own health considerations, she says.

One immediate implication of the Thailand study is that several ongoing perinatal transmission studies will stop their placebo arms, she says. An international UNAIDS study combining AZT and 3TC will drop its placebo arm. Also, a Uganda study giving nevirapine alone in women during labor and to the infant will replace its placebo arm with the short-course Thailand regimen.

If nevirapine proves to be effective, it could be even more significant to developing countries than the short-course AZT regimen because, even at $80 per patient, the AZT regimen is prohibitively expensive in many areas, Mofenson says.

"Not only is nevirapine cheaper, but it is only one dose to the baby and one dose to the woman when she comes for delivery, so she doesn’t have to have prenatal care," she says. "Clearly, it would not have the same efficacy of 076, but even if it were 30% effective, that could be implemented in every country, I think."