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

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).

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 appropriate pediatric dosing and formulations. Some ARVs used as part of the
OBR may be provided by the study. The children will receive an oral dose of ETR twice daily.

Most children will have 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 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.

Inclusion Criteria:

- Confirmed HIV-1 infection as described in the protocol

- At least 2 months of age but younger than 6 years of age at study entry. NOTE:
Children who were born at or sooner than 37 weeks gestational age must be at least 12
weeks of age and at least 46 weeks post-conceptual age at study entry.

- HIV-1 RNA viral load greater than 1,000 copies/mL (within the previous 90 days prior
to screening) and an HIV-1 RNA viral load greater than 1,000 copies/mL at screening

- Treatment-experienced children on a failing combination antiretroviral (ARV) regimen
(containing at least three ARVs) for at least 8 weeks; OR, treatment-experienced
children on a treatment interruption of at least 4 weeks with a history of virologic
failure while on a combination ARV regimen (containing at least three ARVs)

- Ability to swallow etravirine (ETR) whole or dispersed in an appropriate liquid

- Parent or legal guardian able and willing to provide signed informed consent and to
have the child followed at the clinic site

- Availability of sufficient active ARV drugs to create an optimized background regimen
(OBR) consistent with protocol requirements

Exclusion Criteria:

- Evidence of phenotypic resistance to ETR at screening (phenotypic cutoffs of greater
than 10 for loss of sensitivity for cohorts I, II, III)

- Known history of HIV-2 infection in child or child's mother

- Diagnosis of a new Centers for Disease Control (CDC) Stage C (per 1994 Revised
Classification System for Human Immunodeficiency Virus Infection in Children Less than
13 Years of Age) criteria or opportunistic or bacterial infection diagnosed within 30
days prior to screening and not considered clinically stable

- Prior history of malignancy

- Any clinically significant diseases (other than HIV infection) or clinically
significant findings during the screening medical history or physical examination that
in the investigator's opinion would place the child at an unacceptable risk of injury,
render the child unable to meet the requirements of the protocol, compromise the
outcome of this study, or lead to the child being ineligible for participation

- Current Grade 3 or higher of any of the following laboratory toxicities at screening:
neutrophil count, hemoglobin, platelets, aspartate aminotransferase (AST), alanine
aminotransferase (ALT), lipase, or serum creatinine.

- Current or anticipated use of any disallowed medications (listed in the protocol)

- Child's family is unlikely to adhere to the study procedures or keep appointments or
is planning to relocate to a non-IMPAACT study site during the study

- History of nonadherence with ARV medications that in the investigator's opinion could
affect the ability of the child to comply with the protocol/procedures

- Child is currently participating, or has participated within the previous 30 days
prior to screening, in a study with a compound or device that is not commercially
available

- Grade 3 or higher QTc or PR interval prolongation from the electrocardiogram (ECG) at
screening. More information on this criterion can be found in the protocol.