Pharmacokinetic Study of Antiretroviral Drugs and Related Drugs During and After Pregnancy

• Drug parameter: Area under the curve from 0 to 12 hours (AUC 0-12) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
  Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.
  
  
• Drug parameter: Area under the curve from 0 to 24 hours (AUC 0-24) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
  Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.
  
  
• Drug parameter: Maximum concentration (Cmax) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
  Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.
  
  
• Drug parameter: Pre-dose concentration (Cdose) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
  Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.
  
  
• Drug parameter: Minimum concentration (Cmin) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
  Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.
  
  
• Drug parameter: Time after administration of drug when maximum plasma concentration is reached (Tmax) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
  Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.
  
  
• Drug parameter: Clearance over systemic availability (Cl/F) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
  Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.
  
  
• Drug parameter: Volume of distribution over systemic availability (V/F) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
  Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.
  
  
• Drug parameter: Half-life (t1/2) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
  Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.
  
  
• ARV concentrations in vaginal secretions [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
  Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.
  
  
• ARV concentrations in plasma [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
  Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.
  
  
• For contraceptives: plasma concentration [ Time Frame: Measured at 2-12 weeks postpartum (prior to contraceptive initiation) and again 6-7 weeks after contraceptive initiation. ] [ Designated as safety issue: No ]
  

• Ratio of cord blood concentration to maternal blood concentration [ Time Frame: Measured at time of delivery ] [ Designated as safety issue: No ]
  
• Ratio of unbound/total drug concentrations [ Time Frame: Measured at time of delivery ] [ Designated as safety issue: No ]
  Ratio will be measured for the highly-bound ARVs, including atazanavir, darunavir, efavirenz, etravirine, lopinavir, nelfinavir, rilpivirine, and tipranavir
  
  
• Rate of detection of study drugs in vaginal secretions [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
  Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.
  
  
• Ratio of vaginal drug concentrations to simultaneous blood concentrations [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
  Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.
  
  
• Rate of detection of HIV RNA/DNA in vaginal secretions and comparison to level in blood [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
  Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.
  
  
• ARV exposure (as measured by area under the curve or other PK parameters) during pregnancy and postpartum according to genotype [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
  Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.
  
  
• Adverse events of grade 3 or higher [ Time Frame: Measured through 24 weeks postpartum ] [ Designated as safety issue: Yes ]
  
• Infant neurological events of grade 1 or higher [ Time Frame: Measured through 24 weeks of life ] [ Designated as safety issue: Yes ]
  
• Adverse pregnancy outcome: preterm birth [ Time Frame: Measured through delivery ] [ Designated as safety issue: Yes ]
  
• Adverse pregnancy outcome: low birth weight [ Time Frame: Measured at delivery ] [ Designated as safety issue: Yes ]
  
• Adverse pregnancy outcome: fetal demise [ Time Frame: Measured through 24 weeks postpartum ] [ Designated as safety issue: Yes ]
  
• Adverse pregnancy outcome: congenital anomalies [ Time Frame: Measured through 24 weeks of life ] [ Designated as safety issue: Yes ]
  
• Infant HIV infection status [ Time Frame: Measured through 24 weeks of life ] [ Designated as safety issue: No ]
  

Pregnant women experience unique physiological changes that may result in clinically significant alterations in drug PKs. Unfortunately, there have been few clinical trials to study the PKs of ARV, TB, and hormonal contraceptive drugs in pregnant women. The development of appropriate dosing regimens for the HIV-infected pregnant woman is critical to the health of both mother and fetus. Overdosing may lead to maternal adverse events and increased risk of fetal toxicity, while underdosing may lead to inadequate virologic control, increased risk of developing drug resistance mutations, and a higher rate of perinatal HIV transmission. This study will evaluate dosing regimens that are most effective in preventing perinatal HIV transmission and in maintaining the health of both mother and fetus; evaluate the PKs of ARVs used during pregnancy; evaluate TB drugs used during pregnancy, both in women who are HIV-positive and also taking ARVs and in women who are HIV-negative and not taking ARVs; and evaluate the PKs of hormonal contraceptive medications taken along with ARVs.

There will be four main groups of study arms: HIV-infected pregnant women taking ARVs without TB treatment, HIV-infected pregnant women taking ARVs with TB treatment, HIV-uninfected pregnant women taking no ARVs with TB treatment, and HIV-infected pregnant women taking ARVs with postpartum hormonal contraceptives. Participants will not receive medications through this study—they will continue on ARV, TB, and/or contraceptive medications prescribed by their health care providers.

Women who are 20 0/7 weeks to 34 6/7 weeks pregnant will be enrolled in this study and will remain in the study for 24 weeks after delivery. Postpartum women will be enrolled at 2 to 12 weeks after delivery and followed until 6 to 7 weeks after starting contraceptives. Infants will be followed until 24 weeks of life. At all study visits, women will undergo a medical history, a physical exam, and blood collection. At some visits, women in some arms will undergo a vaginal swab. Blood collection from the mother and the detached umbilical cord will occur during delivery. Intensive PK sampling will be performed at study visits during the second and third trimester of pregnancy and between 2 and 3 weeks, 2 and 8 weeks, or 6 and 12 weeks postpartum, with the first sampling occurring within 72 hours of enrollment. The timing of antepartum and postpartum PK samplings will vary by study arm. Additional study visits may occur depending on the ARV drug regimen prescribed.