Clinical Research Needs

These clinical research issues are relevant to the United States and other developed countries, as the current guidelines do not attempt to address the complex research needs or antiretroviral prophylaxis recommendations for resource-limited international settings. Study findings continue to evolve rapidly, and research needs and clinical practice will require continued reassessment over time.

Evaluation of Drug Safety and Pharmacokinetics Many pregnant women with HIV infection in the United States are receiving combination antiretroviral therapy for their own health care as well as standard ZDV prophylaxis to reduce perinatal HIV transmission. Additionally, recent data indicate that antenatal use of potent antiretroviral combinations capable of reducing plasma HIV RNA copy number to very low or undetectable levels near the time of delivery may lower the risk of perinatal transmission to less than 2% (81, 100). While the number of antiretroviral agents and combination regimens used for treatment of infected individuals is increasing rapidly, the number of drugs evaluated in pregnant women remains limited.

Preclinical evaluations of antiretroviral drugs for potential pregnancy- and fetal-related toxicities need to be completed for all existing and new antiretroviral drugs. More data are needed regarding the safety and pharmacokinetics of antiretroviral drugs in pregnant women and their neonates, particularly when used in combination regimens. Additionally, further research is needed on whether there are differing effects of intensive combination treatment on viral load in various body compartments, such as plasma and genital tract secretions, and how this may relate to risk of perinatal transmission.

Continued careful assessment for potential short- and long-term consequences of antiretroviral drug use during pregnancy for both the woman and her child is important. Consequences of particular concern include mitochondrial dysfunction, hepatic, hematologic and other potential end-organ toxicities, development of antiretroviral drug resistance, and/or adverse effects on pregnancy outcome. Because the late consequences of in utero antiretroviral exposure for the child are unknown, innovative methods need to be developed to detect possible rare late toxicities of transient perinatal antiretroviral drug exposure that may not be observed until later in childhood, adolescence, or in adulthood.

Assessment of Drug Resistance

The risk of emerging drug resistance during pregnancy or the postpartum period requires further study. The administration of single drug ZDV for prophylaxis of transmission may increase the incidence of ZDV resistance mutations in women with viral replication that is not maximally suppressed. Administration of drugs for which a single point mutation can confer genotypic resistance, such as nevirapine and lamivudine, to pregnant women with inadequate viral suppression may result in the development of virus with genotypic drug resistance in a significant proportion of the women (171-173). The clinical consequences of emergence of genotypic resistance during pregnancy or in the postpartum period with respect to risk of transmission of resistant virus and future treatment options requires further assessment.

Optimizing Adherence

The complexity of combination antiretroviral regimens as well as drugs for prophylaxis against opportunistic infections often leads to poor adherence among HIV-infected persons. Innovative approaches are needed to address ways to improve adherence for women with HIV infection during and following pregnancy and to ensure that infants receive zidovudine prophylaxis.

Role of Cesarean Section Among Women with Nondetectable Viral Load or with Short Duration of Ruptured Membranes

Elective cesarean delivery has increased among women with HIV infection following the demonstration that delivery prior to labor and membrane rupture can reduce intrapartum HIV transmission (124, 125, 174). Whether elective cesarean delivery provides clinically significant benefit among infected women with low or undetectable viral load on combination antiretroviral therapy, as well as the maternal and infant morbidity and mortality associated with operative delivery, requires further study. Additionally, data from a meta-analysis by the International Perinatal HIV Group indicate that the risk of perinatal transmission increases by 2% for every one hour increase in duration of membrane rupture in infected women with < 24 hours of membrane rupture (175). Therefore, further study is also needed to evaluate the role of non-elective cesarean delivery for reducing perinatal transmission in women with very short duration of ruptured membranes and/or labor.

Management of Premature Rupture of Membranes

With evidence that increasing duration of membrane rupture is associated with an increasing transmission risk (175), more study is needed to define appropriate management of pregnant women with HIV infection who present with ruptured membranes at different points in gestation.

Approaches to offering Rapid Testing at Delivery to Late Presenting Women

One of the groups still at high risk for transmitting HIV to their infants include those women who have not received antenatal care and were not offered HIV counseling and testing. The feasibility of offering counseling and rapid HIV testing to women of unknown HIV status who present in labor requires further study. Additionally, the efficacy and acceptability of intrapartum/postpartum or postpartum infant interventions to reduce the risk of intrapartum transmission by women first identified as infected with HIV during delivery needs to be assessed.

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