Transcript Once-Daily Regimen of FTC, DDI, EFV in ARV

Once-Daily Regimen of FTC,
DDI, EFV in ARV TherapyNaïve Children
PACTG 1021
Organization
• Pediatric AIDS Clinical Trials Group
– NIAID and NICHD sponsored
• Drug and expertise provided by:
– Triangle Pharmaceuticals – Gilead Sciences
– Bristol Myers Squibb
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
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
Patient Characteristics
3-12 years
13+ years
Overall
N=
21
16
37
Female
52%
38%
46%
AA
52%
75%
62%
Latino
33%
13%
24%
CD4 Count (med)
365 cells/μl
288 cells/μl
310 cells/μl
CD4 % (med)
18%
16%
17%
Viral Load (med)
81,450
40,690
47,775
Regimen (Once Daily)
• FTC 6 mg/kg (maximum 200 mg)
• ddI 240 mg/m2 (maximum 400 mg)
– Oral suspension or ddI enteric coated beadlet
capsules
• Efavirenz – Dosing Table
– Oral solution (30 mg/ml)
– Capsules (50/100/200 mg)
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
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 old
Adolescent
Liquid
30.8 h.μg/ml
-
Caps
46.5 h.μg/ml
61 h.μg/ml
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])
Viral Response
1
0.9
P
r
o
p
o
r
t
i
o
n
0.8
0.7
0.6
<400
<50
0.5
0.4
0.3
0.2
0.1
0
0
12
24
36
48
Week
60
72
84
96
CD4 Counts and %
Baseline Wk 16
CD4 CT 310
(median)
CD4 % 17
(median)
Wk 48
Wk 96
513.5
566
673
26
33
32
Median Change in CD4 Ct & %
400
20
18
C 350
D
4 300
16
C
14 D
4
12
C 250
o
u
200
n
t
150
10
8
G
a 100
i
n 50
6
0
0
4
2
4
16
24
36
48
Week
60
72
84
96
%
G
a
i
n
CD4 Ct
CD4 %
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
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%
Acknowledgement
• Thank you to study volunteers and their
families
• Thank you to clinic staff of the 16 sites
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.
•
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Mary Elizabeth Smith, M.D.
Leslie K. Serchuk, M.D.
•
•
•
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Joyce Kraimer, M.S.
Alberto A. Ortiz, M.S.
Linda Draper
Paul Tran, R.Ph.
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Patricia Flynn, M.D.
Ram Yogev, M.D.
Stephen Spector, M.D
Coleen Cunningham, M.D.
Elaine Abrams, M.D.
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Melissa Scites, R.N.
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Ruth Dickover, Ph.D.
Adrianna Weinberg, M.D.
John Rodman, Pharm.D.
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H. Robert Blum, Ph.D.
Gregory E. Chittick
Laurie Reynolds