Evaluating the Safety and Tolerability of Etravirine in HIV-1 Infected Infants and Children
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used as part of
      combination antiretroviral therapy (ART) for infants and children, but NNRTI resistance is
      increasing, leading to treatment failure. This study tested the safety, tolerability, and
      dosing levels of etravirine (ETR), a new NNRTI.
    

Detailed description: 
      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 was tested for safety, tolerability, and appropriate dosing.

      Children were 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 younger than 1 year of age

      Children in all three cohorts were 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).

      Children received 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 were based on clinical status, treatment history, resistance data, and
      availability of appropriate pediatric dosing and formulations. The children received an oral
      dose of ETR twice daily.

      Most children had 11 visits: at screening, entry (Day 0), Day 14 (intensive pharmacokinetic
      [PK] visit), and at Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Most visits included a physical
      exam, giving a medical history, discussion of adherence, and blood and urine collection. The
      screening and intensive PK visits also included an electrocardiogram (ECG). During the
      intensive PK visit, the child had blood drawn approximately 7 times over 12 hours. After the
      Week 48 visit, children entered the long-term follow-up phase of the study and have a visit
      every 12 weeks for up to 5 years. These follow-up visits included giving a medical history
      and undergoing a physical exam and blood draw.
    

Intervention name(s): Etravirine (ETR)
Intervention type(s): Drug
Intervention description(s): ETR was administered as 25-mg scored tablets and/or 100-mg tablets swallowed whole or dispersed in an appropriate liquid vehicle following a meal. Children took the specified dose orally twice daily within 30 minutes following a meal. Dose was decided according to dosing tables in protocol.
Intervention MeSH terms: Etravirine
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment