Safety and Effectiveness of Emtricitabine, Efavirenz, and Didanosine in HIV Infected Children Who Have Taken Few or No Anti-HIV Drugs

Anti-HIV treatment options are limited for pediatric patients because combination therapies
recommended for adults may not be appropriate for children or adolescents. Few PIs are
available in formulations appropriate for pediatric patients, and complex dosing schedules
and food requirements may be detrimental to treatment adherence. A once-daily regimen of the
NRTIs ddI and FTC and the nonnucleoside reverse transcriptase inhibitor (NNRTI) EFV has been
shown safe and well tolerated in adults.

This Phase I/II open label study evaluated the long-term safety and efficacy of a ddI, FTC,
and EFV regimen in pediatric patients. All study patients were either absolutely naive to
antiretroviral therapy or had received less than or equal to 56 days perinatal prophylaxis or
less than 7 days of cumulative antiretroviral therapy prior to study entry, and had a plasma
screening plasma HIV-1 RNA levels >= 5000 copies/mL. This study was written to characterize
the disposition of FTC, determine the PK data for ddI-EC QD, comparing the bio-availability
of the enteric coated formulation with ddI pediatric powder for oral solution, and to provide
insight into the age related pharmacokinetics differences observed in this and other studies.

HIV infected pediatric patients were stratified into three age Groups: Group 1: 90 days to <3
years of age; Group 2: 3 years to 12 years of age (inclusive); and Group 3: 13 to 21 years of
age (inclusive). The initial study doses for the triple drug regimen was FTC, 6 mk/kg up to a
maximum of 200 mg once daily, for EFV, the dose for age Group 1 was determined in PACTG 382
and dose adjusted for body size, and the doses for age Groups 2 and 3 were defined in the
dosing table of the protocol of up to a maximum of 600 mg once daily as a capsule or 720 mg
as an oral solution; for ddI, 240 mg/m2 up to a maximum of 400 mg once daily. Comparison of
age groups was not required as per the protocol.

Patients were followed for a maximum of 192 weeks; all patients were to receive ddI, EFV, and
FTC together once daily. Study visits occurred at study entry, Weeks 2,and 4, and every 4
weeks thereafter. Blood collection, medical history assessment, and a physical exam occurred
at all visits; urine collection occurred at selected visits. Intensive pharmacokinetic (PK)
studies was done at Weeks 2 and 12 to determine if dose adjustments were required for any of
the drugs. If virologic failure was determined, PK studies was repeated 4 weeks after
adjustments in therapy. Parents or guardians were asked to complete treatment adherence
questionnaires at some visits. Some patients were also asked to participate in an additional
PK study after Week 16 or week 96.

Inclusion Criteria:

- HIV infected

- Antiretroviral naive OR have received no more than 56 days of drugs to prevent
mother-to-child transmission of HIV OR have received less than 7 total days of
antiretroviral therapy

- Viral load of 5,000 copies/ml or more

- Any Center for Disease Control (CDC) classification and immune status

- Able to swallow study medications

- Parent or guardian willing to provide informed consent, if applicable

- Willing to use acceptable forms of contraception

- female subjects of childbearing potential with a negative serum beta human chronic
gonadotropin

Exclusion Criteria:

- Allergic to study medications or their formulations

- Kidney disease

- Positive for hepatitis B or C

- Acute opportunistic infection (OI) or bacterial infection requiring treatment at study
entry

- Taking drugs to treat tuberculosis

- Taking anti-HIV drugs other than those included in this study

- Hemoglobin >= grade 3 at screening

- Absolute Neutrophil counts >= grade 2 at screening

- Platelets >= Grade 2 at screening

- Bilirubin >= Grade 2 at screening

- SGOT (AST), SGPT(ALT) >= Grade 2 at screening

- Non-fasting triglycerides >= Grade 2 at screening. Confirmed by a 2nd determination
>=100 mg/dl at fasting state

- Pancreatic amylase or total amylase+ lipase >= Grade 2 at screening

- Taking any investigational drugs

- Anti-cancer drugs within 1 year of study screening

- Serious medical event within 21 days of study screening

- Active or history of pancreatitis

- Require certain medications. Patients requiring short courses of steroids (less than
14 days) for asthma are not excluded.

- Active or history of significant peripheral neuropathy

- Difficulty with food or severe chronic diarrhea within 30 days before study entry

- Unable to eat at least 1 meal per day (or to feed at least 3 times per day, for
infants) because of chronic nausea, vomiting, swallowing problems, or stomach upset

- Unable to swallow oral medications

- Pregnant or breastfeeding