More than a year after the introduction of protease inhibitors for the treatment of HIV infection, the federal government has released a series of documents that attempt to provide principles and guidelines for the use of antiretroviral therapies. In general the documents cover the issues of when to start, when to change and what therapies to use. The underlying premise is that HIV infection should almost always be treated with a combination of at least three drugs that include a protease inhibitor and two nucleoside analogs. The recommendations for the treatment of pregnant women appear in both the guidelines for the treatment of adults and in a separate document focused solely on pregnant women. Unfortunately, both documents dance around the issues of when HIV-positive women should begin treatment and what they should use during pregnancy.

Principle number 8 from the "Report of the NIH Panel to Define Principles of Therapy of HIV Infection" says that "women should receive optimal antiretroviral therapy regardless of pregnancy status," further explaining that, "in general, pregnancy should not compromise optimal HIV therapy for the mother." By optimal therapy the panel means the timely use of combination therapy. The problem is the lack of research on the safety and efficacy of the available drugs during pregnancy, with the exception of AZT, 3TC and nevirapine. Pregnant women are left to make treatment decisions in a vacuum of reliable scientific information.

The FDA has developed a system to classify drugs based on preclinical and clinical data relevant to their use in pregnancy. Table 1 explains each category and classifies the eleven approved antiretroviral agents and some common OI medications. Table 2 addresses the issue of placental transfer.

Clinical scenarios are presented in the pregnancy guidelines to address specific situations and offer recommendations for the use of antiretroviral drugs to reduce vertical transmission.

For treatment-naive women in the first trimester of pregnancy, it is recommended, if clinically possible, to delay therapy until after 10 to 12 weeks gestation. This recommendation makes sense, since there is no evidence about the safety of use of any antiretroviral during this period. After the first trimester, such women should be offered the three-part ACTG 076 regimen plus other antiretroviral drugs as needed for their own health.

In the case of women who are receiving therapy, the recommendation is that if pregnancy is identified before the end the first trimester, consideration should be given to continuing therapy. If therapy is discontinued during the first trimester, all drugs should be stopped and reintroduced simultaneously to minimize the development of resistance.

If pregnancy is identified after the first trimester in women receiving treatment, then the recommendation is that they should continue. If the current regimen does not include AZT, the addition or substitution of AZT is recommended after 14 weeks. Intrapartum and newborn AZT is recommended regardless of the prebirth antiretroviral regimen.

The thrust of these recommendations is that overall, treatment should continue during pregnancy after the first trimester, but the specifics of the treatment do not go beyond the three-part AZT protocol, which in some situations is clearly suboptimal. More research is needed on the safety and efficacy of all antiretroviral drugs during pregnancy for both the mother and the fetus.

Table 1: HIV/AIDS Drugs during Pregnancy Explanation of FDA classification A: Adequate and well-controlled studies of pregnant women fail to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of risk during later trimesters). B: Animal reproduction studies fail to demonstrate a risk to the fetus and adequate and well-controlled studies have not been conducted. C: Safety in human pregnancy has not been determined, animal studies are either positive for fetal risk or have not been conducted, and the drug should not be used unless the potential benefits outweigh the potential risk to the fetus. D: Positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experiences, but the potential benefits from the use of this drug in pregnant women may be acceptable despite its potential risks. X: Studies in animals or reports of adverse reactions have indicated that the risk associated with the use clearly outweighs any possible benefit.
Pregnancy Category	Antiviral Drug/OI Drug
A	NONE
B	ddI, nelfinavir, ritonavir, saquinavir
C*	AZT, ddC, d4T, 3TC, delavirdine, TMP/SMX, aerosolized pentamidine, indinavir, nevirapine, acyclovir, rifampin, fluconazole
D	NONE
X	NONE
*Some category C drugs that are carcinogenic in animals, such as acyclovir which has been available for many years, have been shown over time to be relatively safe in human pregnancy and to not cause tumors.

Table 2: Drugs' Placental Passage in Humans
Positive	Negative or unknown*
AZT, ddI, d4T, ddC, 3TC, nevirapine	delavirdine, nelfinavir, ritonavir, saquinavir, indinavir
*These may be positive placental passage in animals (simians and rodents), but unknown in humans.