Guidelines for the treatment of HIV infection during pregnancy have increasingly diverged from the general guidelines for HIV treatment: a less aggressive strategy has evolved for the management of HIV infection in pregnant women, although it is important to reduce maternal HIV RNA levels in order to decrease the risk of perinatal transmission. Although therapy is recommended for nonpregnant persons with a CD4+ lymphocyte count below 350 per cubic millimeter or an HIV RNA level above 55,000 copies per millimeter, antiretroviral therapy should be offered to all HIV-infected pregnant women in order to reduce the risk of perinatal transmission. This recommendation is based on the consistent findings that the risk of perinatal transmission increases with increasing maternal HIV RNA levels, that transmission rates are below 2 percent among women receiving highly active antiretroviral therapy, and that the use of multiple agents minimizes the potential for the development of resistance. Scheduled cesarean delivery is recommended for HIV-infected women with HIV RNA levels above 1000 copies per milliliter, but highly active antiretroviral therapy may decrease the need for cesarean delivery.
Zidovudine monotherapy was the first regimen shown to reduce the rate of perinatal transmission of HIV type 1 (HIV-1). Subsequent trials have documented reductions in transmission with shorter courses of zidovudine, intrapartum and neonatal treatment with nevirapine, and treatment with zidovudine–lamivudine (Figure 1). However, the lowest transmission rates have been observed in cohorts receiving highly active antiretroviral regimens — 1.2 percent among the 250 women in the Women and Infants Transmission Study and 1.2 percent among the 494 women in the Pediatric AIDS Clinical Trials Group Protocol 316 study (PACTG 316).
Women with a new diagnosis of HIV infection during pregnancy should be fully evaluated to determine the stage of the HIV infection and to identify any coexisting conditions. If therapy is indicated for maternal health (CD4+ lymphocyte count, >350 cells per cubic millimeter; or HIV RNA level, >55,000 copies per milliliter), the clinician and the patient should discuss these indications, potential regimens, and the need for strict adherence in order to prevent the development of resistance. Even without maternal indications for therapy, initiation of highly active antiretroviral therapy should be considered for the prevention of HIV transmission when the HIV RNA level is above 1000 copies per milliliter. Whenever possible, zidovudine should be used, as in the PACTG 076 study, because of its documented reduction of the risk of perinatal transmission, which is independent of its effect on viral load. The options of continuing therapy during the postpartum period or stopping therapy at the time of delivery should be discussed. The potential risks of short courses of highly active antiretroviral therapy for the prevention of transmission have not been studied. However, the risk of the development of resistant viral strains should be minimized by choosing maximally suppressive regimens and by starting and stopping all agents simultaneously.
The option of zidovudine monotherapy or highly active antiretroviral therapy for the reduction of transmission can be considered for pregnant women with HIV RNA levels below 1000 copies per milliliter. At such RNA levels, the transmission rate was 9.8 percent among 368 untreated women and 1 percent among 834 women receiving zidovudine (P>0.001), indicating a beneficial effect even with low HIV RNA levels. Zidovudine monotherapy for the prevention of transmission was not associated with an increased risk of maternal death or disease progression in follow-up to PACTG 076. No mutations causing high-level resistance were detected in a subgroup of 61 women in PACTG 076 who were selected because of an increased potential for resistance; a mutation causing low-level resistance developed between base line and delivery in 1 of 39 women with paired specimens. Given limited viral replication, resistance is unlikely to develop with monotherapy. No data are available to permit the comparison of women with low pretreatment HIV RNA levels who receive zidovudine with those who receive highly active antiretroviral therapy in terms of transmission rates and long-term outcomes in the mothers and their infants.
Whether pregnancy is a specific indication for resistance testing remains controversial. The guidelines of the Public Health Service for perinatal treatment recommend that resistance testing be performed for the same indications in pregnant women as in nonpregnant adults — specifically, acute infection, viral rebound, or persistent viremia in a patient receiving a highly active antiretroviral regimen. Other groups recommend that resistance testing be performed in all pregnant women with detectable HIV RNA levels, even if they have not been treated, in order to maximize the response to antiretroviral drugs, although there are no data available to demonstrate that resistance testing leads to improvement in outcomes for mothers or infants.
The bars show the longest duration of antiretroviral therapy during pregnancy, labor, and delivery and in the newborn in a given study. Transmission rates listed are for the first analysis point reported. The first four studies listed involved women who were not breast-feeding; most of the women in the remaining studies were breast-feeding. The Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 study compared placebo with oral zidovudine starting at 14 to 34 weeks of gestation, intravenous zidovudine during labor, and oral zidovudine for 6 weeks in the infant. A short-course zidovudine study in Thailand (Thai Short) compared placebo with oral zidovudine starting at 36 weeks of gestation, oral zidovudine intrapartum, and no neonatal therapy. The Perinatal HIV Prevention Trial in Thailand (Thai 4-Group) had a factorial design and included four groups, all of which received oral intrapartum zidovudine; the short antepartum course of zidovudine started at 36 weeks of gestation, and the long course started at 28 weeks of gestation; the short course of oral zidovudine for the infant was 3 days and the long course was 6 weeks. PACTG 316 compared placebo with a single dose of nevirapine in the woman during labor and a single dose in the infant at 48 hours of age; both groups of women had been receiving ongoing antiretroviral therapy during pregnancy, including at least zidovudine. A short-course zidovudine trial in the Ivory Coast and Burkina Faso compared placebo with zidovudine beginning at 36 weeks of gestation, oral zidovudine during labor, and zidovudine for 1 week in the infant. Another short-course zidovudine trial in the Ivory Coast compared placebo with oral zidovudine beginning at 36 weeks of gestation and oral zidovudine during labor. The Perinatal Transmission (PETRA) trial involved four groups: in one, oral zidovudine–lamivudine treatment was started at 36 weeks of gestation, and was given during labor and for 1 week after delivery in mother and infant; in the second, oral zidovudine–lamivudine was given during labor and for 1 week after delivery in mother and infant; in the third, oral zidovudine–lamivudine was given during labor only; and the fourth group received placebo. The HIV Network for Prevention Trials (HIVNET) 012 Trial compared a single dose of nevirapine during labor and a single dose in the infant with oral zidovudine given during labor and in the infant for one week. The South African Intrapartum Nevirapine Trial (SAINT) compared a single dose of nevirapine during labor and a single dose in the infant at 48 hours with oral zidovudine–lamivudine given during labor and for one week in the infant.
The prevalence of resistance mutations in pregnant women varies. No resistance to zidovudine was detected at base line among women in PACTG 076, all of whom had CD4+ lymphocyte counts above 200 per cubic millimeter and most of whom had not received antiretroviral drugs. Conversely, a zidovudine-resistance mutation developed in 25 percent of the women in the Women and Infants Transmission Study who were receiving zidovudine for their own health, and high-level resistance to zidovudine was detected in 10 percent of 142 isolates. Mutations in codon 215, which are associated with high-level resistance to zidovudine, were detected in 9.6 percent of 62 consecutive women in the Swiss Collaborative HIV and Pregnancy Study. No such mutations developed in the 33 women in a New York cohort who delivered before 1997, but such mutations did develop in 9.7 percent of the 31 women in the cohort who delivered between 1997 and 1999; these mutations were detected only in women with previous exposure to zidovudine.
Of 220 pregnant women chosen because of previous exposure to zidovudine, 21.8 percent had a mutation associated with resistance to nucleoside reverse-transcriptase inhibitors, and 17.7 percent had a primary mutation associated with such resistance. A total of 2.3 percent of the 220 had a mutation associated with resistance to nonnucleoside reverse-transcriptase inhibitors, but none had a primary mutation associated with such resistance. A total of 0.5 percent had a primary mutation associated with protease-inhibitor resistance.
In all of these studies, the women who were evaluated for resistance mutations represented a subgroup with detectable HIV RNA and clinical characteristics suggesting an increased risk of resistance. Thus, the rate of resistance mutations in the entire study populations was probably lower.
The detection of mutations associated with resistance to zidovudine or other drugs was not associated with an increased risk of perinatal transmission in PACTG 076, PACTG 185, the Swiss Collaborative HIV and Pregnancy Study, or the Perinatal AIDS Collaborative Transmission Study. In a substudy of the Women and Infants Transmission Study, detection of zidovudine resistance was not significantly associated with transmission according to univariate analysis, but when the data were adjusted for the duration of ruptured membranes and the total lymphocyte count, resistance mutations were found to confer an increased risk of transmission. Women in this cohort (who were studied before 1994) were receiving zidovudine during pregnancy for their own health, and zidovudine was generally not given intravenously during labor or to the infants. Although perinatal transmission of resistant virus has been reported, it is not clear that the presence of mutations increases the risk of transmission. Until further data are available, resistance testing should be performed in HIV-infected pregnant women for the same indications as in nonpregnant patients.
Management of HIV infection in pregnant women who are already receiving antiretroviral therapy depends on the gestational age of the fetus, clinical findings, and the regimen being used. If the pregnancy is discovered after the first trimester, therapy should be continued. A detailed ultrasonographic examination should be performed at 18 to 20 weeks of gestation to confirm the gestational age of the fetus and to screen for detectable anomalies. Options during the first trimester include continuing the regimen; changing the regimen if it includes specific drugs that carry an increased risk, such as efavirenz or delavirdine; or discontinuing all antiretroviral drugs and reinstituting them after the first trimester. This last strategy has the potential to cause viral rebound and might increase the risk of transmission. Decisions should depend on the clinical circumstances and the treatment history. Hydroxyurea should be discontinued during pregnancy, since it is teratogenic in animals and its value in the treatment of HIV is unclear. If antiretroviral therapy must be interrupted during the first trimester, all agents should be discontinued and reinstated simultaneously in order to prevent the development of resistance.
Several options are available for treatment during labor in HIV-infected women who have had no previous antiretroviral therapy. Observational studies found that the use of intravenous zidovudine during labor plus a six-week regimen of oral zidovudine in the infant reduced the rate of transmission: 27 to 31 percent of infants in the untreated group became infected, as compared with 10 percent of those in the treated group. Other studies demonstrated reductions in the rate of transmission with intrapartum and neonatal zidovudine–lamivudine therapy or maternal and neonatal nevirapine therapy (Figure 1). Current guidelines include the combination of zidovudine and nevirapine as an option for such intrapartum and neonatal treatment, although there are no data available to permit an assessment of the efficacy of this regimen in the prevention of transmission.
The addition of intrapartum and neonatal nevirapine to an established antiretroviral regimen during pregnancy did not result in an additional reduction in the rate of perinatal transmission of HIV in the PACTG 316 trial. Furthermore, in a subgroup with detectable HIV RNA levels at the time of delivery, resistance to nevirapine developed in 11 percent of the women. Thus, despite its efficacy in reducing the rate of transmission among previously untreated women, the addition of peripartum nevirapine to the regimens of women who are already receiving antiretroviral therapy is not recommended.
The optimal therapy for infants born to HIV-infected women who have received no antiretroviral therapy has not been determined. Observational data suggest that zidovudine therapy initiated within 48 hours after birth is beneficial. Whether the use of additional agents would further reduce the risk of transmission is unknown, although some clinicians would choose to use combination regimens in such infants — a strategy analogous to that used for postexposure prophylaxis in adults.
Prevention and Treatment of Opportunistic Infections during Pregnancy
Recommendations for prophylaxis against and treatment of opportunistic infections in nonpregnant adults should be followed with slight modification during pregnancy. Prophylaxis against and treatment of Mycobacterium tuberculosis, Pneumocystis carinii, M. avium complex, and Toxoplasma gondii infections during pregnancy are similar to prophylaxis and treatment in nonpregnant adults. Primary prophylaxis against cytomegalovirus infection, mucosal candida infections, and invasive fungal infections is not recommended routinely for nonpregnant persons because of drug toxicity. Treatment of serious infections should not be withheld because of pregnancy; regimens should be chosen in consultation between the obstetrician and a specialist in infectious diseases. Hepatitis B, influenza, and pneumococcal vaccines may be given during pregnancy for the usual indications but should be administered after HIV RNA has been suppressed to undetectable levels with antiretroviral therapy, in order to prevent the increase in the risk of transmission that theoretically accompanies the transient increase in HIV RNA after immunization.
From the Pediatric, Adolescent, and Maternal AIDS Branch, Center for Research on Mothers and Children, National Institute of Child Health and Human Development, Bethesda, Md.
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D. Heather Watts, M.D.
The New England Journal of Medicine