Safety and Pharmacokinetics of Raltegravir in HIV-1-Exposed Newborn Infants at High Risk of Acquiring HIV-1 Infection

• Toxicity endpoint: Adverse events (AEs) of Grade 3 or 4 severity [ Time Frame: Measured from study entry through 6 weeks of life ] [ Designated as safety issue: Yes ]
  
• Toxicity endpoint: death [ Time Frame: Measured from study entry through 6 weeks of life ] [ Designated as safety issue: Yes ]
  
• Toxicity endpoint: Suspected adverse drug reaction (SADR) of Grade 3 or 4 severity [ Time Frame: Measured from study entry through 6 weeks of life ] [ Designated as safety issue: Yes ]
  
• PK endpoint for Cohort 1: maximum concentration (Cmax) of RAL [ Time Frame: Measured within 48 hours of birth, at Day 3 to 4 of life, and at Day 7 to 10 of life ] [ Designated as safety issue: No ]
  
• PK endpoint for Cohort 1: area under the concentration-time curve at the 12-hour dosing internal (AUC12) of RAL [ Time Frame: Measured within 48 hours of birth, at Day 3 to 4 of life, and at Day 7 to 10 of life ] [ Designated as safety issue: No ]
  
• PK endpoint for once-daily dosing in Cohort 2: area under the concentration-time curve at the 24-hour dosing internal (AUC24) [ Time Frame: Measured at Day 3 to 4 of life, Day 14 of life, Day 28 of life, and Week 6. ] [ Designated as safety issue: No ]
  
• PK endpoint for twice-daily dosing in Cohort 2: AUC12 [ Time Frame: Measured at Day 3 to 4 of life, Day 14 of life, Day 28 of life, and Week 6 ] [ Designated as safety issue: No ]
  
• PK endpoint for Cohort 2: geometric mean (GM) trough [ Time Frame: Measured at Day 3 to 4 of life, Day 14 of life, Day 28 of life, and Week 6 ] [ Designated as safety issue: No ]
  

• Toxicity endpoint: AEs of Grade 3 or 4 severity [ Time Frame: Measured from study entry through 24 weeks of age ] [ Designated as safety issue: Yes ]
  
• SADR of Grade 3 or 4 severity [ Time Frame: Measured from study entry through 24 weeks of age ] [ Designated as safety issue: Yes ]
  
• Death [ Time Frame: Measured from study entry through 24 weeks of age ] [ Designated as safety issue: Yes ]
  

Significant progress has been made in the use of antiretroviral (ARV) drugs for the prevention of mother-to-child transmission (PMTCT) of HIV, but new pediatric HIV infections continue. If the diagnosis of HIV infection in a pregnant woman goes unrecognized and ARVs have not been used during pregnancy and labor, ARVs can be used to lower the risk of HIV transmission to the infant. However, it is important to develop new and more effective regimens for post-birth PMTCT.

The integrase inhibitor raltegravir (RAL ) has the potential to play an important role in both the prevention and treatment of HIV in infants at high risk of HIV-1 infection. This study will evaluate the safety and PKs of RAL given to HIV-1-exposed newborns at high risk of acquiring HIV-1 infection. The study also seeks to determine the appropriate dosing regimen of RAL that can be safely given to newborns and infants in the first 6 weeks of life.

The study will enroll 50 mother-infant pairs from the time of delivery through 48 hours of life. Mothers will be followed until discharge from the labor and delivery unit, and infants will be followed for 24 weeks after birth.

Newborns will be assigned non-randomly to 1 of 2 cohorts. A minimum of 12 newborns will be enrolled into Cohort 1. These newborns will receive RAL as oral granules for suspension as a single dose within 48 hours of birth, in addition to standard of care ARV drugs for PMTCT, and a second dose of RAL at 7 to 10 days of life. All newborns in Cohort 1 will undergo a medical history, physical exam, and blood draw at entry and at the Day 3 to 4, Day 7 to 10, Week 2, Week 6, and Week 24 study visits. Cohort 1 newborns will have 3 PK samplings: an intensive PK at the time of the first dose, a random PK at Day 3 to 4, and a limited PK at the time of dose 2.

All data from Cohort 1 will be reviewed and analyzed before any participants are enrolled into Cohort 2. Based on ongoing analyses of PK data and safety information, dosing may be modified.

A minimum of 20 newborns will be enrolled into Cohort 2. These newborns will receive daily RAL starting within 48 hours of birth for 6 weeks, in addition to standard of care ARV for PMTCT. After analyses of PK and safety data from Cohort 1 (as well as ongoing analyses), dosing frequency in this cohort may be changed from once to twice daily, and dosing (amount) may also be changed. All newborns in Cohort 2 will undergo a medical history, physical exam, and blood draw at all study visits. Study visits will occur at entry, Day 3 to 4, Day 14, Day 28, Week 6, Week 8 to 10, and Week 24. Cohort 2 newborns will have four PK samplings: a random PK sample at Day 3 to 4, intensive PK samplings at Day 14 and Day 28, and a random PK sampling at Week 6.