Evaluating the Safety and Tolerability of Etravirine in HIV-1 Infected Infants and Children

• Termination from treatment due to a suspected adverse drug reaction (SADR) [ Time Frame: Measured through Week 48, or for up to 5 years if individual participates in long-term safety follow-up ] [ Designated as safety issue: Yes ]
  
• Adverse events (AEs) of Grade 3 or higher severity [ Time Frame: Measured through Week 48, or for up to 5 years if individual participates in long-term safety follow-up ] [ Designated as safety issue: Yes ]
  
• Death [ Time Frame: Measured through Week 48, or for up to 5 years if individual participates in long-term safety follow-up ] [ Designated as safety issue: Yes ]
  
• Failure to meet PK targets [ Time Frame: Measured at intensive PK visit (within 7-10 days of study drug administration) ] [ Designated as safety issue: No ]
  The area under the plasma concentration-time curve over 12 hours (AUC12h) of ETR will be the PK criterion for determination of the acceptability of the ETR dose.
  
  

• AEs of Grade 3 or higher severity judged to be at least possibly attributable to the study medications [ Time Frame: Measured through Week 48, or for up to 5 years if individual participates in long-term safety follow-up ] [ Designated as safety issue: Yes ]
  
• Confirmed failure to suppress plasma HIV-1 RNA to fewer than 400 copies and failure to achieve at least a 2-log reduction (from baseline) in HIV-1 RNA at Weeks 24 and/or 48 (confirmed in 1 to 4 weeks) [ Time Frame: Measured at Weeks 24 and/or 48 ] [ Designated as safety issue: No ]
  
• Treatment discontinued due to toxicity or virologic failure [ Time Frame: Measured through Week 48, or for up to 5 years if individual participates in long-term safety follow-up ] [ Designated as safety issue: Yes ]
  
• Change in optimized background regimen due to virologic failure [ Time Frame: Measured at entry and at Weeks 8, 12, 24, and 48 ] [ Designated as safety issue: No ]
  
• New onset opportunistic infection (OI) or AIDS diagnosis [ Time Frame: Measured through Week 48, or for up to 5 years if individual participates in long-term safety follow-up ] [ Designated as safety issue: No ]
  
• Decline in absolute CD4 percent of greater than 5 percent any time after 12 weeks of therapy [ Time Frame: Measured at entry and at Weeks 12, 24, and 48 ] [ Designated as safety issue: No ]
  

Use of NNRTI-based regimens as initial therapy for HIV-infected children is increasing, especially in areas where newborns exposed to HIV-1 receive single-dose nevirapine (NVP) as part of prevention of mother-to-child transmission (PMTCT) regimens and/or daily NVP for prevention of transmission through breastfeeding. First-generation NNRTIs have a low genetic barrier to the development of resistance; in two of the most widely used NNRTIs, NVP and efavirenz (EFV), even a single amino acid mutation in the virus can lead to a reduction in the drug's effectiveness. Even short-term use of these NNRTIs, including only a single dose of NVP, can cause NNRTI resistance. Second-generation NNRTIs are needed as part of ARV regimens for newly diagnosed infants and children who have been exposed to single-dose NVP or who have failed their current antiretroviral (ARV) regimens. In this study, the second-generation NNRTI ETR will be tested for safety, tolerability, and appropriate dosing.

Children will be assigned to one of three cohorts based on age:

• Cohort I: At least 2 but younger than 6 years of age
• Cohort II: At least 1 but younger than 2 years of age
• Cohort III: At least 2 months but less than 1 year of age

Children in all cohorts will be treatment experienced, defined as being on a failing combination ARV regimen (containing at least 3 ARVs) for at least 8 weeks or having a treatment interruption of at least 4 weeks with a history of virologic failure while on a combination ARV regimen (containing at least 3 ARVs).

Enrollment will move in a sequential manner, starting with the oldest cohort. All cohorts will begin with enrollment into a mini-cohort of 6 children that will be followed for 4 weeks to assess safety. If the analysis results of the mini-cohort suggest that a higher or lower dose of ETR is needed, a new dose will be agreed upon by the protocol team and 6 new children will be enrolled as a new mini-cohort. If the mini-cohort passes the safety evaluation, 6 additional children will be enrolled to complete the full enrollment for that cohort (12 children) and the mini-cohort for the next younger cohort will open.

Children will receive ETR together with an optimized background regimen (OBR) consisting of at least 2 active agents (a boosted protease inhibitor [PI] and at least 1 additional active ARV drug). OBR will be based on clinical status, treatment history, resistance data, and availability of dosing guidelines. Most children will receive an oral dose of ETR twice daily; some children 2 months to 6 months of age in Cohort III may receive three daily doses.

Most children will have 11 visits: at screening, entry (Day 0), once between Day 7 and Day 12 (intensive pharmacokinetic [PK] visit), and at Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Most visits will include a physical exam, giving a medical history, discussion of adherence, and blood and urine collection. The screening and intensive PK visits will also include an electrocardiogram (ECG). During the intensive PK visit, the child will have blood drawn approximately 7 times over 12 hours. After the Week 48 visit, children will enter the long-term follow-up phase of the study and will have a visit every 12 weeks for up to 5 years. These follow-up visits will include giving a medical history and undergoing a physical exam and blood draw.