Grant: Operating Grant

The use of highly active antiretroviral therapy (HAART) in HIV-infected pregnant women is necessary for preventing disease progression in the mother and transmission of HIV to her fetus. Although pregnant women account for a large portion of patients on these drugs, there is a lack of knowledge which presents risks in that too high a dose may cause maternal or fetal toxicities and too low a dose can lead to treatment failure and risk of fetal HIV infection. Several drug transporters found in the placenta limit fetal exposure to drugs and other noxious chemicals by actively pumping compounds out of the fetal compartment. Over the past 5 years our laboratory has shown that viral and bacterial infections can cause changes in drug transporter levels in the placenta and other tissues. The implications of these changes on maternal drug exposure, safety, and effectiveness are enormous, yet, in spite of this, very little regarding this phenomenon is currently known. Furthermore, virtually nothing is known about the impact of disease on fetal drug exposure. Indeed, co-existing infections are common in HIV-infected pregnant populations worldwide, thus investigating their impact on maternal and fetal exposure to HAART is warranted. Studies within our laboratory over the next 5 years will address: (1) the regulation of placental and maternal drug transporters in HIV and other co-infections and (2) the resultant impact of disease and co-infections on maternal and fetal exposure to HAART therapy. This information will enable us to predict potential drug-disease interactions and will assist in developing drug and dosage guidelines to improve therapy for HIV positive women during pregnancy.