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U.S. Public Health Service Recommendations for Use of Antiretroviral Drugs During Pregnancy
Highlights of a Task Force Report Aimed at Optimizing Maternal Health and Reducing Perinatal Transmission of HIV Infection
In February of 1994, ACTG 076 demonstrated that administration of zidovudine (ZDV, AZT, Retrovir®) to pregnant women and their newborn infants reduced the risk of mother-to-child transmission of HIV infection by nearly 70%. In August of that year the U.S. Public Health Service issued recommendations for use of ZDV to prevent perinatal transmission of the virus. Specifically, the Public Health Service recommended that all HIV-positive women receive oral ZDV (100 mg five times a day) during the second and third trimesters of pregnancy and intravenous ZDV during labor (a one-hour loading dose of 2 mg/kg followed by 1 mg/kg until delivery). All infants born to these women were to be given ZDV in syrup form (2 mg/kg every 6 hours) for the first six weeks of life, beginning 8-12 hours after birth.
In the three years since these guidelines were issued, research has provided us with a much better understanding of the pathogenesis of HIV disease, and technological breakthroughs have provided us with tools to monitor the virus and drugs to suppress it. These advances have led to major changes in the standard of care for HIV-infected adults, and current interventions focus on early initiation of aggressive combination antiretroviral regimens to suppress viral replication, preserve immune function, and discourage the development of drug-resistant viral strains.
Since 1994 we have also seen major advances in our understanding of perinatal HIV transmission. It is now recognized, for example, that most infections occur shortly before or during delivery -- which suggests that there is a "window of opportunity" for effective intervention.
All of these developments have important implications for maternal and fetal health. In the era of HIV RNA assays to measure viral load and triple-drug combination regimens to suppress viral replication, all use of antiretroviral agents in pregnant women must take into account two separate but interconnected issues: optimal therapy for the mother-to-be, and optimal prophylaxis to reduce the risk of perinatal transmission. ZDV is the only antiretroviral agent that has been shown to significantly reduce the likelihood of mother-to-infant transmission, but ZDV monotherapy is no longer recommended for HIV-infected individuals. Or, to put it another way: What is best for the baby, on the basis of the evidence at hand, is not what is best for the mother, on the basis of the evidence at hand.
To reconcile the apparently competing needs of mother and child -- both of whom deserve the best healthcare clinicians can provide -- the Public Health Service has issued updated guidelines for the use of antiretroviral agents during pregnancy (Table). These recommendations have been based on the belief that therapies of known benefit to HIV-positive women should not be withheld during pregnancy unless there are known adverse effects on the mother, the fetus, or the infant -- and these adverse effects outweigh any potential benefit to the woman. In short, optimal antiretroviral therapy in pregnant HIV-positive women should be the same as the therapy provided to non-pregnant adults.
Combination therapy with two nucleoside analogs and a protease inhibitor is the currently recommended standard of care for adults with symptomatic HIV disease, low CD4 counts, or a high viral load. Pregnancy per se should not preclude the use of optimal therapeutic regimens. However, clinicians should be aware that the use of antiretroviral agents in pregnant women is subject to unique considerations, and dosing requirements may change due to the physiologic changes associated with pregnancy and the potential effects of therapy on the fetus and newborn.
Using antiretrovirals during pregnancy
Physical changes that occur during pregnancy may affect the kinetics of drug absorption, distribution, and elimination. During pregnancy, GI transit time becomes prolonged, body water and fat increase, and changes occur in cardiac output, liver and renal blood flow, plasma protein concentrations, sodium reabsorption, and a number of other physiologic processes. Transport of drugs across the placenta, compartmentalization of drugs in the fetus, and biotransformation and elimination of drugs by the fetus can also affect the pharmacokinetics of antiretroviral agents in pregnant women.
At present, there are limited data available on the safety and efficacy of antiretroviral agents during pregnancy. Of the five currently approved nucleoside analogs, only ZDV and lamivudine (3TC) have been evaluated in clinical trials. Both of these drugs are well tolerated at the standard adult doses. A recently completed pilot study of ZDV plus 3TC in pregnant women found that both drugs crossed the placenta, achieving comparable serum concentrations in the mother and the neonate, and no adverse effects were observed in the infants.
Of the two F.D.A.-approved non-nucleoside reverse transcriptase inhibitors, only nevirapine has been administered to pregnant women (as a single 200 mg oral dose during labor). This drug crosses the placental barrier particularly effectively, reaches neonatal blood concentrations equivalent to those seen in the mothers, and has no observable adverse effects on the mothers or their infants. A study is under way to assess the effectiveness of chronic dosing with nevirapine, beginning at 38 weeks gestation, but the data are not yet available.
Data are similarly scanty for the protease inhibitors, although a number of teams are currently studying the safety and efficacy of indinavir, ritonavir, and nelfinavir in combination with ZDV and 3TC. As the findings of these clinical trials are announced, we will report them in HIV Newsline.
Monitoring viral load
The clear correlation between HIV RNA level and disease progression in non-pregnant adults suggests that viral load should be measured at least as often during pregnancy as is recommended for individuals who aren't pregnant, i.e. every three to four months, which is roughly once a trimester. Data on the correlation between viral load and risk of perinatal transmission have been conflicting, with some studies suggesting an absolute correlation and others showing a less emphatic association. What we do know is that transmission has been observed across the entire range of HIV RNA levels. Mother-to-infant HIV transmission has even occurred when women had undetectably low levels of HIV RNA.
At the present time, it is not known if the potent new antiretroviral regimens, which achieve near-total suppression of viral replication, will be more effective than ZDV monotherapy in reducing the risk of perinatal transmission of HIV. HIV RNA assays will help clinicians make decisions about the treatment of pregnant patients, but because ZDV has proven effective in blocking mother-to-infant transmission regardless of maternal HIV RNA level, ZDV should be part of every pregnant woman's antiretroviral regimen irrespective of her viral load.
Evaluating and counseling the pregnant patient
The initial clinical work-up of an HIV-positive pregnant woman should include an assessment of her disease status: her degree of immunodeficiency (determined by CD4 count), risk of disease progression (determined by plasma HIV RNA level), history of prior or current antiretroviral therapy, and gestational age.
For women who are antiretroviral-naïve, decisions regarding when and how to initiate therapy should be the same as for non-pregnant individuals. For women who are on therapy, decisions regarding the cessation or alteration of therapy should be the same as for patients who are not pregnant. Because we have little data on the long-term effects of combination antiretroviral therapy in pregnant women, fetuses, and neonates, clinicians must involve their pregnant patients in the decision-making process.
In particular, clinicians should tell their patients what is known -- and what is not known -- about the potential effects of antiretroviral drugs on the fetus and newborn, including the lack of long-term data on the use of any of the available agents during pregnancy. The patient should also be told what antiretroviral regimen the clinician would recommend as optimal therapy if she were not pregnant.
This discussion with the patient should describe -- in simple, straightforward lay language -- what clinical information we do have about the risks and benefits of antiretroviral therapy during pregnancy. It is important to place the hypothetical risks of therapy in perspective to the proven benefits for the patient's own health. And it is essential that the patient understand the established benefits of the three-part ZDV prophylaxis regimen in reducing the risk that she will transmit HIV infection to her infant.
Back to the August 1997 HIV Newsline contents page.
This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.