XIV: PHARMACOLOGIC CONSIDERATIONS IN HIV-INFECTED PREGNANT PATIENTS
Paul Pham, PharmD, and Patricia Barditch-Crovo, MD


I. LIST OF TABLES

Table 14-1: Antiretrovirals

Table 14-2: Commonly Used Antimicrobials for the Treatment and Prevention of Opportunistic Infections in HIV-Infected Patients

Table 14-3: Safety of Commonly Used Antimicrobials

Table 14-4: Drug Interactions of Antimicrobials

Table 14-5: Clinically Pertinent Food-Drug Interactions

Table 14-6: Drugs of Special Consideration in Women

Table 14-7: Alternative/Complimentary Medication to Avoid in Pregnancy


II. INTRODUCTION

The decision to administer drugs to a pregnant woman is largely based on the therapeutic benefit to the mother and/or fetus vs. the perceived risk to the developing fetus. Clinicians are usually advised to avoid prescribing drugs for pregnant patients because human safety data in pregnancy are lacking for many medications. However in some clinical situations the benefits far outweigh the risks. These are important considerations when selecting agents to treat patients with human immunodeficiency virus (HIV), to prevent its transmission, and to prevent associated opportunistic infections.

     There is limited information concerning the safety of many antiretrovirals in pregnancy. Mutagenicity and teratogenicity studies in animals are the basis for most safety in pregnancy data. Animals are administered doses 5 to 20 times higher than those given to humans; clinical applicability is not always evident.

     It is now standard care to treat HIV-infected patients with an “antiretroviral cocktail,” making it increasingly difficult to assess the safety of a single anti-retroviral agent. More prospective clinical data are needed. Clinicians are encouraged to report all in utero exposures to The Antiretroviral Pregnancy Registry (1-800-258-4263), a collaborative effort between the National Institutes of Health, the Centers for Disease Control and Prevention, and pharmaceutical companies. Outcome data compiled from the Registry are used to monitor birth defects.

     The Food and Drug Administration (FDA) has developed a classification system to help clinicians choose agents safe for use in pregnancy (Tables 14-1, 14-2, 14-3, and 14-6).

III. RISKS OF ANTIRETROVIRAL DRUGS IN PREGNANCY

Certain antiretroviral agents should be avoided during pregnancy, either because of effects inherent to the drug itself, or the potential for dangerous interactions. Administration of efavirenz to pregnant cynomolgus monkeys is associated with anencephaly, unilateral anophthalmia, microophthalmia and cleft palate in newborns (DuPont, 1998). Hydroxyurea produces mutagenesis and teratogenesis in many animal species; it should not be given during pregnancy (Shepard, 1992).

     Antiretroviral therapy is often complicated by side effects in relatively healthy HIV-infected nonpregnant adults that could be exacerbated in pregnancy or put the fetus at risk. Protease inhibitors, for example, have been associated with the development of glucose intolerance and even diabetes mel-litus. Hyperglycemia in pregnancy leads to increased risk of macrosomia, fetal distress, preeclampsia, and stillbirth (Ndiaye, 1997). In patients taking indinavir, 10% develop indirect bilirubinemia (i.e., > 2.5%), and nephrolithiasis has been reported in 5–15% (Merck, 1998). Any of these adverse effects will complicate a pregnancy.

     Because many patients turn to complimentary or alternative therapies, it is important to take a complete medication history, including over-the-counter drugs and nutritional supplements. St John’s wort lowers trough indinavir drug concentrations by 81% when administered concurrently (Piscitelli, 2000). Because St. John’s wort induces cytochrome P450 3A enzymes, it will likely decrease levels of other protease inhibitors and non-nucleoside reverse tran-scriptase inhibitors. Therefore, St. John’s wort should not be taken with anti-retroviral medications. Because safety data for herbal alternative therapies are scarce, these agents should be avoided during pregnancy. Table 14-6 summarizes data on alternative therapies to avoid during pregnancy.

IV. BENEFITS OF ANTIRETROVIRAL DRUGS IN PREGNANCY: DRUGS TO CONSIDER

One example in which the benefit far outweighs the risk of drug administration during pregnancy is evident in the use of zidovudine (AZT) in preventing perinatal HIV transmission (ACTG study 076) (Connor, 1995).. Administration of AZT to the pregnant HIV-infected mother after the first trimester, during labor, after labor, and to the newborn reduced the perinatal acquisition of HIV. In addition, uninfected infants exposed to AZT in this study and followed to a median age of 3.9 yr have not shown a significant difference in growth, neurologic development, or immune status when compared with unin-fected infants exposed to placebo (Hanson, 1999). The use of AZT during pregnancy and delivery has become the standard of care in the United States; however because of its high cost, its administration during pregnancy is not feasible in developing countries.

     The HIVNET 012 trial compared the administration of one dose of nevi-rapine given orally to the mother during labor followed by one dose of nevirap-ine to the infant within 72 hr after birth with the administration of AZT during labor followed by AZT to the infant for 7 days. The 14–16-wk postdelivery data showed that although both regimens were well tolerated, 25.1% of infants in the AZT arm and 13.1% of infants in the nevirapine arm were infected with HIV (p=.0006)(Guay, 1999). Although long-term safety data are not currently available for nevirapine, this regimen may provide a simple and inexpensive regimen to prevent perinatal transmission of HIV in less developed countries. The current guidelines state that pregnancy per se should not preclude use of optimal therapeutic regimens. Therefore pregnant women should be treated according to standard guidelines for antiretroviral therapy in adults, with sustained reduction of viral load as the primary objective(CDC, 1998).

V.  PHARMACOKINETICS OF ANTIRETROVIRAL DRUGS IN PREGNANCY

Although many physiologic changes occur during pregnancy, few trials have been conducted to evaluate their clinical significance on the pharmacokinetics of commonly used drugs. Physiologic changes that may affect drug pharmaco-kinetics include delayed gastric emptying, decreased intestinal motility, increased volume of distribution (an average increase of 8 L), increased renal blood flow (by 25–50%), and glomerular filtration rate (by 50%) (Davidson, 1974; Dunihoo, 1992; Parry, 1970). The serum half-life of nevirapine is reduced from 66 hr in nonpregnant women to 45 hr in pregnant women; this decrease is not likely to be clinically significant (Mirochnick, 1998). Pregnancy does not change the pharmacokinetics of AZT, 3TC, and ddI (Moodley, 1998; Schuman, 1990; Wang, 1999).

     The absorption and pharmacokinetics of many of the anti-HIV drugs are affected by food. Table 14-5 lists pertinent food-drug interactions that are probably as valid for pregnant women as for a nongravid population.

     Table 14-1, on the following pages, provides a quick reference on dosing recommendations, FDA Pregnancy Risk Classification, animal teratogenicity, and human experience in pregnancy for the most commonly prescribed drugs in the treatment of HIV infection.

 

Table 14-1: Antiretrovirals


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Table 14-2: Commonly Used Antimicrobials for the Treatment and Prevention of Opportunistic Infections in HIV-Infected Patients

 

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Table 14-3: Safety of Commonly Used Antimicrobials

 

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Table 14-4: Drug Interactions of Antimicrobials

 

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Table 14-5: Clinically Pertinent Food-Drug Interactions

 

Table 14-6: Drugs of Special Consideration in Women

 

Table 14-7: Alternative/Complimentary Medication to Avoid in Pregnancy

 

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Table 14-7: Alternative/Complimentary Medication to Avoid in Pregnancy - continued

 

Table 14-7: Alternative/Complimentary Medication to Avoid in Pregnancy - continued

 

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