Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents

US Health & Human Services, December 1998

Considerations for Antiretroviral Therapy in the HIV-Infected Pregnant Woman

Women who are in the first trimester of pregnancy and who are not receiving antiretroviral therapy may wish to consider delaying initiation of therapy until after 10 to 12 weeks gestation, since this is the period of organogenesis when the embryo is most susceptible to potential teratogenic effects of drugs; the risks of antiretroviral therapy to the fetus during that period are unknown. However, this decision should be carefully considered and discussed between the health care provider and the patient and should include an assessment of the woman's health status and the potential benefits and risks of delaying initiation of therapy for several weeks. If clinical, virologic or immunologic parameters were such that therapy would be recommended for nonpregnant individuals, many of the Panel members would recommend initiating therapy regardless of gestational age. Nausea and vomiting in early pregnancy affecting the ability to adequately take and absorb oral medications may be a factor in the decision regarding treatment during the first trimester.

Some women already receiving antiretroviral therapy may recognize their pregnancy early enough in gestation that concern for potential teratogenicity may lead them to consider temporarily stopping antiretroviral therapy until after the first trimester. There are insufficient data to support or refute teratogenic risk of antiretroviral drugs when administered during the first 10-12 weeks of gestation. However, a rebound in viral levels would be anticipated during the period of discontinuation and this rebound could theoretically be associated with increased risk of early in utero HIV transmission or could potentiate disease progression in the woman^[25]. Although the effects of all antiretroviral drugs on the developing fetus during the first trimester are uncertain, most experts recommend continuation of a maximally suppressive regimen even during the first trimester. If antiretroviral therapy is discontinued during the first trimester for any reason, all agents should be stopped simultaneously to avoid development of resistance. Once the drugs are reinstituted, they should be introduced simultaneously for the same reason.

The choice of which antiretroviral agents to use in pregnant women is subject to unique considerations (see Principle 8). There are currently minimal data available on the pharmacokinetics and safety of antiretroviral agents during pregnancy for drugs other than ZDV. In the absence of data, drug choice will need to be individualized based on discussion with the patient and available data from preclinical and clinical testing of the individual drugs. The FDA pregnancy classification for all currently approved antiretroviral agents and selected other information relevant to the use of antiretroviral drugs in pregnancy is shown in Table XVII. It is important to recognize that the predicitive value of in vitro and animal screening tests for adverse effects in humans is unknown. Many drugs commonly used to treat HIV infection or its consequences may have positive findings on one or more of these screening tests. For example, acyclovir is positive on some in vitro assays for chromosomal breakage and carcinogenicity and is associated with some fetal abnormalities in rats; however, data on human experience from the Acyclovir in Pregnancy Registry indicate no increased risk of birth defects to date in infants with in utero exposure to acyclovir^[26].

Of the currently approved nucleoside analogue antiretroviral agents, the pharmacokinetics of only ZDV and 3TC have been evaluated in infected pregnant women to date^[27,28]. Both appear to be well tolerated at the usual adult doses and cross the placenta, achieving concentrations in cord blood similar to those observed in maternal blood at delivery. All the nucleosides except ddl have preclinical animal studies that indicate potential fetal risk and have been classified as FDA pregnancy category C (defined in Table XVII); ddl has been classified as category B. In primate studies, all the nucleoside analogues appear to cross the placenta, but ddl and ddC appear to have significantly less placental transfer (fetal to maternal drug rations of 0.3 to 0.5) than do ZDV, d4T and 3TC (fetal to maternal drug ratios >0.7)^[29]. Of the non-nucleoside reverse transcriptase inhibitors, only nevirapine administered once at the onset of labor has been evaluated in pregnant women^[30]. The drug was well-tolerated after a single dose, and crossed the placenta and achieved neonatal blood concentrations equivalent to those in the mother. The elimination of nevirapine administered during labor in the pregnant women in this study was prolonged (mean half-life following a single dose, 66 hours) compared to non-pregnant individuals (mean half-life following a single dose, 45 hours). Data on multiple dosing during pregnancy are not yet available. Delavirdine has not been studied in Phase I pharmacokinetic and safety trials in pregnant women. In premarketing clinical studies, outcomes of 7 unplanned pregnancies were reported. Three of these were ectopic pregnancies, and three resulted in healthy live births. One infant was born prematurely with a small ventricular septal defect to a patient who received approximately 6 weeks of treatment with delavirdine and ZDV early in the course of pregnancy. Efavirenz (Sustiva) is a newly approved non-nucleoside reverse transcriptase inhibitor. In a developmental toxicity study, pregnant cynomolgus monkeys received efavirenz from gestational day 20 to 150 in a dose 30 mg/kg twice daily, which was expected to achieve plasma concentrations which approximate those in humans given 600 mg daily^[31]. Three of 20 fetuses had gross malformations: anencephaly and unilateral anophthalmia in one fetus; microphthalmia in another; and cleft palate in a third (Table 16). No malformations were seen in the concurrent control group of animals. No data exist regarding the teratogenic potential of other NNRTIs in primates; the absence of these data should not be interpreted to mean that these other agents are safe to use in pregnancy.

Although studies of combination therapy with protease inhibitors in pregnant infected women are in progress, there are currently no data available regarding drug dosage, safety and tolerance in pregnancy. In mice, indinavir has significant placental passage, but in rabbits, little placental passage was observed. Ritonavir has been shown to have some placental passage in rats. There are some special theoretical concerns regarding the use of indinavir late in pregnancy. Indinavir is associated with side effects (hyperbilirubinemia and renal stones) that theoretically could be problematic for the newborn if transplacental passage occurs and the drug is administered shortly before delivery. This is because the immaturity of the metabolic enzyme system of the neonatal liver would likely be associated with prolonged drug half-life leading to extended drug exposure in the newborn, which could lead to potential exacerbation of physiologic neonatal hyperbilirubinemia. Additionally, due to immature neonatal renal function and the inability of the neonate to voluntarily ensure adequate hydration, high drug concentrations and/or delayed elimination in the neonate could result in a higher risk for drug crystallization and renal stone development than observed in adults. These concerns are theoretical and such effects have not been reported; because the half-life of indinavir in adults is short, these concerns may only be relevant if drug is administered near the time of labor. Gestational diabetes is a pregnancy-related complication that can develop in some women; administration of any of the four currently available protease inhibitors has been associated with new onset diabetes mellitus, hyperglycemia or exacerbation of existing diabetes mellitus in HIV-infected patients^[32]. Pregnancy is itself a risk factor for hyperglycemia and it is unknown if the use of protease inhibitors will exacerbate this risk. Health care providers caring for infected pregnant women who are receiving protease inhibitor therapy should be aware of this possibility, and closely monitor glucose levels in their patients as well as instruct their patients in recognizing the early symptoms of hyperglycemia.

To date, the only drug that has been shown to reduce the risk of perinatal HIV transmission in ZDV when administered according to the following regimen: orally administered antenatally after 14 weeks gestation and continued throughout pregnancy, intravenously administered during the intrapartum period, and to the newborn for the first 6 weeks of life^[33]. This chemoprophylactic regimen was shown to reduce the risk of perinatal transmission by 66% in a randomized, double blind clinical trial, pediatric ACTG 076^[34]. There are insufficient data available at present to justify the substitution of any antiretroviral agent other than ZDV for the purpose of reducing perinatal HIV transmission; further research will address this question. For the time being, if combination antiretroviral drugs are administered to the pregnant woman for treatment of her HIV infection, ZDV should be included as a component of the antenatal therapeutic regimen whenever possible, and the intrapartum and neonatal ZDV components of the chemoprophylactic regimen should be administered for the purpose of reducing the risk of perinatal transmission. If a woman does not receive ZDV as a component of her antenatal antiretroviral regimen (e.g. because of prior history of non-life threatening ZDV-related severe toxicity or personal choice), intrapartum and newborn ZDV should continue to be recommended; when use of ZDV is contraindicated in the woman, the intrapartum component may be deleted but the newborn component is still recommended. ZDV and d4T should not be administered together due to potential pharmacologic antagonism. When d4T is a preferred nucleoside for treatment of a pregnant woman, it is recommended that antenatal ZDV not be added to the regimen; however, intrapartum and neonatal ZDV should still be given.

The antenatal dosing regimen used in the perinatal transmission prophylaxis trial PACTG 076 was ZDV 100 mg administered five times daily, and was selected based on the standard ZDV dosage for adults at the time the study was designed in 1989 (see Table XVIII). However, recent data have indicated that administration of ZDV three times daily will maintain intracellular ZDV triphosphate at levels comparable with those observed with more frequent dosing^[35,36]. Comparable clinical response also has been observed in clinical trials among persons receiving ZDV twice daily^[37-39]. Thus, the current standard ZDV dosing regimen for adults is 200 mg three times daily, or 300 mg twice daily. A less frequent dosing regimen would be expected to enhance maternal adherence to the ZDV perinatal prophylaxis regimen, and therefore is an acceptable alternative antenatal dosing regimen for ZDV.

In a recent short-course antenatal/intrapartum ZDV perinatal transmission prophylaxis trial in Thailand, administration of ZDV 300 mg twice daily for 4 weeks antenatally and 300 mg every 3 hours orally during labor was shown to reduce perinatal transmission by approximately 50% compared to placebo^[40]. The lower efficacy of the short-course 2-part ZDV prophylaxis regimen studied in Thailand compared to the 3-part ZDV prophylaxis regimen used in PACTG 076 and recommended for use in the U.S. could result from the shorter antenatal duration of ZDV, oral rather than intravenous administration during labor, lack of treatment for the infant, or a combination of these factors. In the United States, identification of HIV-infected pregnant women before or as early as possible during the course of pregnancy and use of the full 3-part PACTG 076 ZDV regimen is recommended for prevention of perinatal HIV transmission.

The time-limited use of ZDV alone during pregnancy for chemoprophylaxis of perinatal transmission is controversial. The potential benefits of standard combination antiretroviral regimens for treatment of HIV infection should be discussed with and offered to all pregnant HIV-infected women. Some women may wish to restrict exposure of their fetus to antiretroviral drugs during pregnancy but still wish to reduce the risk of transmitting HIV to their infant. For women in whom initiation of antiretroviral therapy for treatment of their HIV infection would be considered optional (e.g. CD4⁺ count >500/mm³ and plasma HIV RNA less than 10,000-20,000 RNA copies/ml), time-limited use of ZDV during the second and third trimesters of pregnancy is less likely to induce the development of resistance due to the limited viral replication existing in the patient and the time-limited exposure to the antiretroviral drug. For example, the development of resistance was unusual among the healthy population of women who participated in Pediatric (P)-ACTG 076^[41]. The use of ZDV chemoprophylaxis alone during pregnancy might be an appropriate option for these women. However, for women with more advanced disease and/or higher levels of HIV RNA, concerns about resistance are greater and they should be counseled that a combination antiretroviral regimen that includes ZDV for reducing transmission risk would be more optimal for their own health than use of ZDV chemoprophylaxis alone.

Monitoring and use of HIV-1 RNA for therapeutic decision-making during pregnancy should be performed as recommended for non-pregnant individuals. Transmission of HIV from mother to infant can take place at all levels of maternal HIV-1 RNA. In untreated women, higher HIV-1 RNA levels correlate with increased transmission risk. However, in ZDV-treated women this relationship is markedly attenuated^[32]. ZDV is effective in reducing transmission regardless of maternal HIV RNA level. Therefore, the use of the full ZDV chemoprophylaxis regimen, including intravenous ZDV during delivery and the administration of ZDV to the infant for the first six weeks of life, along or in combination with other antiretrovirals, should be discussed with and offered to all infected pregnant women regardless of their HIV-1 RNA level. Health care providers who are treating HIV-infected pregnant women are strongly encouraged to report cases of prenatal exposure to antiretroviral drugs (either administered alone or in combinations) to the Antiretroviral Pregnancy Registry. The registry collects observational, nonexperimental data regarding antiretroviral exposure during pregnancy for the purpose of assessing potential teratogenicity. Registry data will be used to supplement animal toxicology studies and assist clinicians in weighing the potential risks and benefits of treatment for individual patients. The registry is a collaborative project with an advisory committee of obstetric and pediatric practitioners, staff from CDC and NIH, and staff from pharmaceutical manufacturers. The registry allows the anonymity of patients, and birth outcome follow-up is obtained by registry staff from the reporting physician. Referrals should be directed to Antiretroviral Pregnancy Registry, Post Office Box 13398, Research Triangle Park, NC 27709-3398; telephone 919-483-9437 or 1-800-258-4263; fax 1-800-800-1052.