Considerations for Antiretroviral Therapy in the HIV-Infected Pregnant Woman

Antiretroviral treatment recommendations for HIV-infected pregnant women are based on the belief that therapies of known benefit to women should not be withheld during pregnancy unless the risk of adverse effects outweighs the expected benefit to the woman. Combination antiretroviral therapy is the recommended standard treatment for HIV-infected non-pregnant adults. Additionally, a three-part regimen of ZDV, given orally starting at 14 weeks gestation and continued throughout pregnancy, intravenously during labor and to the newborn for the first six weeks of life, reduced the risk of perinatal transmission by 66% in a randomized, double-blind clinical trial (PACTG protocol 076) (20) and is recommended for all pregnant women (167). Pregnancy should not preclude the use of optimal therapeutic regimens. However, recommendations regarding the choice of antiretroviral drugs for treatment of infected women are subject to unique considerations including a) potential changes in dosing requirement resulting from physiologic changes associated with pregnancy, b) potential effects of antiretroviral drugs on the pregnant woman, c) effect on the risk of perinatal HIV ransmission,and d) the potential short- and long-term effects of the antiretroviral drug on the fetus and newborn, which may not be known for many antiretroviral drugs (167) (See Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-1 Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States). As discussed further below, the decision to use any antiretroviral drug during pregnancy should be made by the woman following discussion with her health care provider regarding the known and unknown benefits and risks to her and her fetus. Long-term follow-up is recommended for all infants born to women who have received antiretroviral drugs during pregnancy.

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.

Standard combination antiretroviral therapy is recommended as initial therapy for HIV-infected pregnant women whose clinical, immunologic or virologic status would suggest the need for treatment if non-pregnant. When initiation of antiretroviral therapy would be considered optional based on current guidelines for treatment of non-pregnant individuals but HIV-1 RNA levels are >1,000 copies/mL, infected pregnant women should be counseled regarding the potential benefits of standard combination therapy and should be offered such therapy including the three-part ZDV chemoprophylaxis regimen (Table 24). Although such women are at low risk for clinical disease progression if combination therapy is delayed, antiretroviral therapy that successfully reduces HIV-1 RNA levels to below 1,000 copies/mL substantially lowers the risk of perinatal transmission (168-170) and limits the need to consider elective cesarean delivery as an intervention to reduce transmission risk (167) (See Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-1 Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States).

Use of antiretroviral prophylaxis has been shown to provide benefit in preventing perinatal transmission even for infected pregnant women with HIV-1 RNA levels <1,000 copies/mL. In a meta-analysis of factors associated with perinatal transmission among women who had infectedinfants despite having HIV-1 RNA <1,000 copies/mL at or near delivery, transmission was only 1.0% among women receiving ZDV prophylaxis compared to 9.8% among those receiving no antiretroviral treatment (168). 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 regardless of viral load, and is recommended for all pregnant women with HIV-1 RNA levels >1,000 copies/mL. However, 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. Additionally, for women with HIV-1 RNA levels <1,000 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 ZDV resistance was unusual among the healthy population of women who participated in PACTG 076 (21). The use of ZDV chemoprophylaxis alone during pregnancy might be an appropriate option for these women. When combination therapy is given principally to reduce perinatal transmission and would have been considered optional for treatment if non-pregnant, consideration may be given to discontinuing therapy postnatally, with the decision to reinstitute treatment based on standard criteria for non-pregnant individuals. If drugs are discontinued postnatally, all drugs should be stopped simultaneously. Discussion regarding the decision to continue or stop combination therapy postpartum should occur prior to initiation of therapy during pregnancy.

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 in humans when administered during the first 10–12 weeks of gestation. However, treatment with EFV should be avoided during the first trimester because significant teratogenic effects in rhesus macaques were seen at drug exposures similar to those representing human exposure. Hydroxyurea is a potent teratogen in a variety of animal species and should also be avoided during the first trimester.

There is concern that temporary discontinuation of antiretroviral therapy could result in a rebound in viral levels that theoretically could be associated with increased risk of early in utero HIV transmission or could potentiate disease progression in the woman (167). 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.

There are currently limited data available on the pharmacokinetics and safety of antiretroviral agents during pregnancy for drugs other than ZDV (see “Safety and Toxicity of Individual Antireroviral Agents in Pregnancy”). In the absence of data, drug choices 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 23. It is important to recognize that the predictive 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 (172).

When combination antiretroviral therapy is given during pregnancy, ZDV should be included as a component of antenatal therapy whenever possible. There may be circumstances where this is not feasible, such as the occurrence of significant ZDV-related toxicity. In addition, women receiving an antiretroviral regimen that does not contain ZDV but who have HIV-1 RNA levels that are consistently very low or undetectable have a very low risk of perinatal transmission and there may be concerns that the addition of ZDV to the current regimen could compromise adherence to the regimen. Regardless of the antepartum antiretroviral regimen, intravenous intrapartum ZDV and the standard six week course of ZDV for the infant is recommended. If the woman has not received ZDV as a component of her antenatal therapeutic antiretroviral regimen, intravenous ZDV should still be administered to the pregnant woman during the intrapartum period when feasible. Additionally, in women receiving combination antiretroviral treatment, the maternal antenatal antiretroviral treatment regimen should be continued on schedule as much as possible during labor to provide maximal virologic effect and to minimize the chance of development of drug resistance. Because ZDV and d4T should not be administered together due to potential pharmacologic antagonism, options for women receiving oral d4T as part of their antenatal therapy include continuation of oral d4T during labor without intravenous ZDV, or withholding the oral d4T during the period of intravenous administration during labor.

Toxicity related to mitochondrial dysfunction has been reported in infected patients receiving long-term treatment with nucleoside analogues, and may be of particular concern for pregnant women. Symptomatic lactic acidosis and hepatic steatosis may have a female preponderance (123). Additionally, these syndromes have similarities to the rare but life-threatening syndromes of acute fatty liver of pregnancy and hemolysis, elevated liver enzymes and low platelets (the HELLP syndrome) that occur during the third trimester of pregnancy. Some data suggest that a disorder of mitochondrial fatty acid oxidation in the mother or her fetus during late pregnancy may play a role in the etiology of acute fatty liver of pregnancy and HELLP syndrome (173, 174), and possibly contribute to susceptibility to antiretroviral-associated mitochondrial toxicity.

It is unclear if pregnancy augments the incidence of the lactic acidosis/hepatic steatosis syndrome reported in non-pregnant individuals receiving nucleoside analogue treatment. Bristol-Myers Squibb has reported three maternal deaths due to lactic acidosis, two with and one without accompanying pancreatitis, in women who were either pregnant or postpartum and whose antepartum therapy during pregnancy included d4T and ddI in combination with other
antiretroviral agents (either a PI or NVP) (175). All cases were in women who were receiving treatment with these agents at the time of conception and continued for the duration of pregnancy; all presented late in gestation with symptomatic disease that progressed to death in the immediate postpartum period. Two cases were also associated with fetal demise. Non-fatal
cases of lactic acidosis in pregnant women have also been reported.

Because pregnancy itself can mimic some of the early symptoms of the lactic acidosis/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, these cases emphasize the need for physicians caring for HIV-infected pregnant women receiving nucleoside analogue drugs to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogue drugs should have hepatic enzymes and electrolytes assessed more frequently during the last trimester of pregnancy and any new symptoms should be evaluated thoroughly. Additionally, because of the reports of several cases of maternal mortality secondary to lactic acidosis with prolonged use of the combination of d4T and ddI by HIV-infected pregnant women, clinicians should prescribe this antiretroviral combination during pregnancy with caution and generally only when other nucleoside analogue drug combinations have failed or caused unacceptable toxicity or side effects (175).

The antenatal ZDV 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 (Table 24). However, data indicate that administration of ZDV three times daily will maintain intracellular ZDV triphosphate at levels comparable with those observed with more frequent dosing (176, 177). Comparable clinical response also has been observed in clinical trials among persons receiving ZDV twice daily (178-180). 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 prophylaxis.

In a 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 (181). 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.

Monitoring and use of HIV-1 RNA for therapeutic decision-making during pregnancy should be performed as recommended for non-pregnant individuals. Data from untreated as well as ZDV-treated infected pregnant women indicate that HIV-1 RNA levels correlate with risk of transmission (20, 169, 170). However, although the risk of perinatal transmission in women with HIV-1 RNA below the level of assay quantitation appears to be very low, transmission from mother to infant has been reported in women with all levels of maternal HIV-1 RNA. Additionally, antiretroviral prophylaxis is effective in reducing transmission even among women with low RNA levels (20, 168). The mechanism by which antiretroviral prophylaxis reduces transmission is likely multifactorial. Reduction in maternal antenatal viral load is likely an important component of prophylaxis. However, in addition, pre- and post-exposure prophylaxis of the infant is provided by passage of antiretroviral drugs across the placenta, resulting in inhibitory drug levels in the fetus during and immediately following the birth process (182); the extent of transplacental passage varies between antiretroviral drugs (Table 23). Additionally, while there is general correlation between plasma and genital tract viral load, discordance has also been reported (183-185); in addition, differential evolution of viral sequence diversity occurs between the peripheral blood and genital tract (185, 186). Studies are needed to define the relationship between viral load suppression by antiretroviral therapy in plasma and levels of HIV in the genital tract, and the relationship between these compartment-specific effects and the risk of perinatal HIV transmission. 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, in combination with other antiretrovirals or alone in selected cases, 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, 115 North Third Avenue, Suite 306, Wilmington, NC 28401; telephone 910-251-9087 or 1-800-258-4263; fax 1-800-800-1052.

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