1. Once-Daily Regimen of FTC, DDI, EFV in ARV Therapy- Naïve Children PACTG 1021

2. Organization Pediatric AIDS Clinical Trials Group –NIAID and NICHD sponsored Drug and expertise provided by: –Triangle Pharmaceuticals – Gilead Sciences –Bristol Myers Squibb

3. Justification Once a day regimen improves compliance Long half-life drugs might be more forgiving Side effect profiles for all three drugs (FTC, ddI, EFV) individually are manageable

4. Patient Population ARV Naïve (allowed perinatal prophylaxis) Three cohorts, n=37: –90 days to <3 years (not reported at this meeting – currently enrolling) –3 years to 12 years [21 subjects] –13 years to 21 years [16 volunteers] Enrollment between 9/18/2001 and 10/23/2002 Data cut off – August 2, 2004

5. Patient Characteristics 3-12 years13+ yearsOverall N=211637 Female52%38%46% AA52%75%62% Latino33%13%24% CD4 Count (med)365 cells/μl288 cells/μl310 cells/μl CD4 % (med)18%16%17% Viral Load (med)81,45040,69047,775

6. Regimen (Once Daily) FTC 6 mg/kg (maximum 200 mg) ddI 240 mg/m 2 (maximum 400 mg) –Oral suspension or ddI enteric coated beadlet capsules Efavirenz – Dosing Table –Oral solution (30 mg/ml) –Capsules (50/100/200 mg)

7. Study Design Open label, Phase I-II Every 4 week visits through week 96 Intense PK at weeks 2, 8/12, and time of discontinuation Multiple spot levels drawn Intention to Treat Analysis Endpoints: Safety, tolerance, proportion <50 HIV copies/ml; <400 HIV copies/ml

8. PK Result FTC and ddI pharmacokinetics provided anticipated AUCs EFZ – Initial levels below anticipated for children ≤12 years receiving oral solution, so dose increased –Median AUCs (prior to adjustment) Format≤12 years oldAdolescent Liquid30.8 h.μg/ml- Caps46.5 h.μg/ml61 h.μg/ml

9. Adverse Events 2 children discontinued before 2 weeks due to rash (one Grade 3, one Grade 2) No subjects with laboratory abnormalities attributed to drug regimen –1 Grade 4 hypoglycemia, 2 grade 3 CPK considered “possibly” related 2 subjects had Grade 3 symptoms attributed to the regimen (rash; dizziness [wk1 – resolved spontaneously])

10. Viral Response

11. CD4 Counts and % BaselineWk 16Wk 48Wk 96 CD4 CT (median) 310513.5566673 CD4 % (median) 17263332

12. Median Change in CD4 Ct & %

13. Discontinuations 10/37 Subjects discontinued treatment –2 Rashes –3 Virologic failure –2 Adolescents incarcerated –2 Subjects felt visits were inconvenient –1 Subject moved out of the country No Deaths or new Category C diagnoses

14. Conclusions Once daily Combination of FTC/ddI/EFZ well tolerated – 2 subjects with rash Efficacy appeared to be good: –Using ITT, 72% <50 copies at week 96 –Only 3/37 discontinued because of viral failure CD4 response was very positive: median CD4 % went from 17% to 32%

15. Acknowledgement Thank you to study volunteers and their families Thank you to clinic staff of the 16 sites

16. PACTG 1021 Study Team Ross E. McKinney, Jr, M.D. Mobeen Rathore, M.D. Chengcheng Hu, Ph.D. Paula Britto, M.S. Michael Hughes, Ph.D. Mary Elizabeth Smith, M.D. Leslie K. Serchuk, M.D. Joyce Kraimer, M.S. Alberto A. Ortiz, M.S. Linda Draper Paul Tran, R.Ph. Patricia Flynn, M.D. Ram Yogev, M.D. Stephen Spector, M.D Coleen Cunningham, M.D. Elaine Abrams, M.D. Melissa Scites, R.N. Ruth Dickover, Ph.D. Adrianna Weinberg, M.D. John Rodman, Pharm.D. H. Robert Blum, Ph.D. Gregory E. Chittick Laurie Reynolds