Revised CDC guidelines underscore mother’s health

Update provides latest info on treatment advances

Four years after providing HIV-positive pregnant women with treatment guidance for preventing perinatal transmission, the Centers for Disease Control and Prevention has updated its recommendations, providing more detailed information on how mothers can walk the fine line between caring for their own health and ensuring the safety of their newborns.

"The reason we have revised the guidelines is because there have been advances in treatment," says 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. "We also have more follow-up information on babies and mothers that is reassuring, but also some new animal data that is not so reassuring in terms of the potential for carcinogenesis."

The new guidelines, published recently as a supplement in the Morbidity and Mortality Weekly Report, are the result of a large public health task force working for the past year to bring together the latest findings on the efficacy of antiretroviral therapy, the toxicity associated with these drugs, and long-term effects on child health.1

The 1994 recommendations addressed the landmark ACTG 076 trial documenting that zidovudine (AZT) preventive therapy could reduce perinatal transmission by nearly 70%. Studies since then have confirmed the efficacy of this therapy, and treatment has been extended to pregnant women with advanced disease, low CD4 counts, and prior AZT therapy. Most recently, a short-course regimen of AZT in Thai women has shown that a much-reduced course of AZT can lower perinatal transmission by 50%. (See article on Thai study implications on p. 42.)

The success of the 076 regimen has dramatically reduced the prevalence of mother-child transmission in the United States to as low as 3% to 4%, Mofenson tells AIDS Alert. At the same time, however, the standard for antiretroviral therapy has dramatically changed in adults, such that monotherapy AZT is no longer recommended. How combination therapy affects perinatal transmission and the health of newborns is not known, and yet health officials are now recommending that pregnant women should not refrain from seeking the most effective treatment for themselves.

"Monotherapy is no longer used for treatment of non-pregnant women, nor should it be used for pregnant individuals," Mofenson says. "We thought we needed to address this issue and tell people we don’t know a lot about these drugs, but being pregnant is not a reason to give treatment that would be considered inappropriate in a non-pregnant person."

One unintended result of the 1994 guidelines, which did not mention the use of other antiretroviral drugs, was that patients and their physicians interpreted them to mean that treatment during pregnancy should be limited to AZT, she says.

"Evidently many people misinterpreted the 94 guidelines as meaning that AZT monotherapy is the only thing you should use during pregnancy," she explains. "They never said that, but there clearly was an interpretation that they did."

Consequently, the update includes a section discussing what is known about the new therapies and overtly emphasizing the need for women to seek treatment for their own health first. Nonetheless, pregnant women are responsible for another life and are aware of the delicate balance of providing themselves with the most effective treatment while at the same time limiting adverse consequences to their babies. To help sort out the dilemmas and decisions they face, the guidelines present four scenarios or situations women may find themselves in, discussing the limited data that should be considered before making treatment decisions.

The most common — and difficult — situation clinicians are now presented with are women who are already on drugs and who become pregnant while on treatment, not infrequently combination therapy. This scenario provides little data to determine the right decision. However, because of the unique features of AZT, health officials recommend that this drug should be incorporated into the patient’s regimen after the first trimester. If the patient is in the first trimester of pregnancy and decides to stop therapy until the second trimester, all drugs should be stopped and then restarted in order to prevent resistance from developing.

"AZT should be a component wherever possible," Mofenson says, "and if AZT is not a component antenatally, then intrapartum and newborn AZT should still be given — that is very critical."

Although researchers still haven’t pinpointed when transmission from mother to child occurs, it is now believed that it occurs most often close to or during labor, so even treatment in late-stage pregnancy is likely to prevent transmission, Mofenson notes.

"Many people feel that an important component is pre- and postexposure prophylaxis," she explains. "By giving the drug intravenously to the mother you are actually loading the baby up, so when it goes through the birth canal it has drug on board. And then by giving it six weeks postpartum you are protecting the baby against any potentially infected maternal cells that cross to the baby during labor."

Other drugs being studied

What appears to make AZT so effective in preventing perinatal transmission is that it is metabolized into the active triphosphate in the placenta itself. No other nucleoside analogues studied so far appear to do that, Mofenson says. Consequently, other regimens being studied in pregnant women contain AZT in combination with another drug.

A large study enrolling 1,500 patients in East Africa is looking at AZT in combination with 3TC. One arm of the study provides short-course — one week only — therapy to the infant postpartum. A second arm provides only intrapartum and postpartum therapy, while a third arm is intrapartum only. Results of the study should be known this summer, Mofenson adds.

The non-nucleoside reverse transcriptase inhibitor nevirapine is being studied in two trials. The first trial is giving U.S. women the drug on top of the 076 regimen. It is given orally to the mother at the onset of labor and to the infant at 48 hours after birth. The second study, in Uganda, provides a single-dose treatment given to the mother during labor and to the infant six weeks after birth.

There are numerous Phase I trials looking at the safety and efficacy of combination therapy using a protease inhibitor, combining AZT and 3TC with either indinavir, ritonavir, saquinavir, or nelfinavir.

One concern with possible long-term implications centers on recent findings from animal studies showing that AZT causes cancer. Although AZT is the only drug in which transplacental carcinogenicity studies have been completed, researchers are concerned about possible similar findings in other antiretroviral drugs, particularly other nucleoside analogues, that have shown similar in vitro findings for cancer, Mofenson says. The CDC has responded to these studies by saying that the risk of cancer is not great enough to warrant discontinuing AZT.

Close to meeting the 2% goal

When the 076 trial was completed, it was credited for reducing perinatal transmission by an estimated 66%. Only 8% of infants became infected by treated mothers, compared to 25% to 30% for infants whose mothers did not receive treatment. There were factors, however, that may have caused an underestimation of its efficacy, Mofenson notes, adding that in recent studies using the 076 regimen, rates have been as low as 3%.

The most striking evidence is a statewide study in North Carolina where women were given all three components of 076 and transmission was only 3%. A similar study in New York, presented at the 5th Conference on Retroviruses and Opportunistic Infection in January, showed a transmission rate of 4.5%. Also, ACTG 185, a study of pregnant women with advanced HIV disease, combined 076 with passive immunization with an HIV antibody immunoglobulin. The study had to be stopped because the transmission rate was so low — 4.8% — that the trial could not answer the question it was designed for.

"Our goal in the United States is to lower transmission to under 2%," Mofenson notes, "and frankly I think we are almost there. With AZT alone we are down to 3% to 4% if taken for the full regimen."

Whether adding other drugs to the regimen can further reduce the rate is unknown. Mofenson points out that if pre- and postexposure prophylaxis are the only critical elements in preventing transmission, then it may not be possible to lower the rate to less than 3% to 4%. However, other factors, particularly a mother’s viral load, could be associated with transmission. Although the 076 trial didn’t appear to show that viral load predicted transmission, that study was not designed to best answer the question and ACTG 185 should help provide an answer.

Knowing the impact of a mother’s viral load is important because if it is a factor, transmission rates could be lowered simply by treating pregnant women with combination therapy, Mofenson says.

"It could be that simply by having combination therapies given for maternal health indications, we could have the ability to lower transmission to under 2% without doing anything else," she says.

Reference

1. Centers for Disease Control and Prevention. Public health service task force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV for maternal health and for reducing perinatal HIV transmission in the United States. MMWR 1998; 47/RR-2.